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Jiang SM, Li XJ, Wang ZL, Chen ZW, Liu ZL, Li Q, Chen XL. Role of autophagy in rejection after solid organ transplantation: A systematic review of the literature. World J Transplant 2025; 15:103163. [DOI: 10.5500/wjt.v15.i3.103163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 01/21/2025] [Accepted: 02/06/2025] [Indexed: 04/18/2025] Open
Abstract
Organ transplantation has long been recognized as an effective treatment for end-stage organ failure, metabolic diseases, and malignant tumors. However, graft rejection caused by major histocompatibility complex mismatch remains a significant challenge. While modern immunosuppressants have made significant strides in reducing the incidence and risk of rejection, they have not been able to eliminate it completely. The intricate mechanisms underlying transplant rejection have been the subject of intense investigation by transplant immunologists. Among these factors, autophagy has emerged as a key player. Autophagy is an evolutionarily conserved mechanism in eukaryotic cells that mediates autophagocytosis and cellular protection. This process is regulated by autophagy-related genes and their encoded protein families, which maintain the material and energetic balance within cells. Additionally, autophagy has been reported to play crucial roles in the development, maturation, differentiation, and responses of immune cells. In the complex immune environment following transplantation, the role and mechanisms of autophagy are gradually being revealed. In this review, we aim to explore the current understanding of the role of autophagy in solid organ rejection after transplantation. Furthermore, we delve into the therapeutic advancements achieved by targeting autophagy involved in the rejection process.
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Affiliation(s)
- Shu-Min Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Xue-Jiao Li
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Zi-Lin Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Zhi-Wei Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Zhi-Long Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Qiang Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - Xiao-Long Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
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Sun L, Zhao X, Tan X, Song L, Ma Z, Wang J, Lan P, Chen S, Chen G. High mobility group box-1 protein-mediated class II major histocompatibility complex transactivator superenhancers are critical for dendritic cell-trained immunity in acute-to-chronic progression of allograft rejection. Am J Transplant 2025; 25:954-968. [PMID: 39884654 DOI: 10.1016/j.ajt.2025.01.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 12/31/2024] [Accepted: 01/22/2025] [Indexed: 02/01/2025]
Abstract
Chronic allograft rejection is mainly mediated by indirect recognition. Dendritic cells (DCs), as the major antigen-presenting cells in indirect recognition, exhibit an enhanced antigen-presenting ability in chronic rejection, but the specific mechanism is still unclear. Here, we found that pretreatment with high mobility group box-1 protein (HMGB1) in vivo can induce trained immunity in DCs. These trained DCs demonstrated an enhanced ability to present alloantigen, accelerating allograft rejection in a CTLA4-Ig-induced chronic rejection model by upregulating the expression of major histocompatibility complex (MHC)-II and class II major histocompatibility complex transactivator (CIITA) molecules. Mechanistically, we found that HMGB1 promoted the formation of superenhancers (SEs) of CIITA, epigenetically reprogramming DCs and promoting trained immunity. The SE inhibitor JQ1 reduced the expression of CIITA and MHC-II in DCs, thereby delaying the occurrence of chronic rejection. Interestingly, we identified HMGB1 as a specific inducer of SE formation in a newly named SEa region of CIITA. Targeted knockout of the CIITA's SEa region inhibited HMGB1-induced trained immunity in DCs. Taken together, our data confirm that HMGB1 can induce the formation of the SEs of CIITA, promote trained immunity in DCs, and accelerate allograft rejection, thus offering a new potential target for the treatment of chronic rejection.
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Affiliation(s)
- Lingjuan Sun
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xiangli Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xiaosheng Tan
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Liu Song
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhibo Ma
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Jingzeng Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Peixiang Lan
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Song Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
| | - Gang Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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3
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Diebold M, Mayer KA, Hidalgo L, Kozakowski N, Budde K, Böhmig GA. Chronic Rejection After Kidney Transplantation. Transplantation 2025; 109:610-621. [PMID: 39192468 PMCID: PMC11927446 DOI: 10.1097/tp.0000000000005187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 08/29/2024]
Abstract
In kidney transplantation, ongoing alloimmune processes-commonly triggered by HLA incompatibilities-can trigger chronic transplant rejection, affecting the microcirculation and the tubulointerstitium. Continuous inflammation may lead to progressive, irreversible graft injury, culminating in graft dysfunction and accelerated transplant failure. Numerous experimental and translational studies have delineated a complex interplay of different immune mechanisms driving rejection, with antibody-mediated rejection (AMR) being an extensively studied rejection variant. In microvascular inflammation, a hallmark lesion of AMR, natural killer (NK) cells have emerged as pivotal effector cells. Their essential role is supported by immunohistologic evidence, bulk and spatial transcriptomics, and functional genetics. Despite significant research efforts, a substantial unmet need for approved rejection therapies persists, with many trials yielding negative outcomes. However, several promising therapies are currently under investigation, including felzartamab, a monoclonal antibody targeting the surface molecule CD38, which is highly expressed in NK cells and antibody-producing plasma cells. In an exploratory phase 2 trial in late AMR, this compound has demonstrated potential in resolving molecular and morphologic rejection activity and injury, predominantly by targeting NK cell effector function. These findings inspire hope for effective treatments and emphasize the necessity of further pivotal trials focusing on chronic transplant rejection.
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Affiliation(s)
- Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Katharina A. Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Luis Hidalgo
- HLA Laboratory, Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | | | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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Gonzalez-Nolasco B, Lancia HH, Carnel-Amar N, Wang X, Prunevieille A, Van Dieren L, Lellouch AG, Cetrulo CL, Benichou G. Adenosine triphosphate-mediated signaling of P2X7 receptors controls donor extracellular vesicle release and major histocompatibility complex cross-decoration after allotransplantation. Am J Transplant 2025; 25:674-681. [PMID: 39694144 PMCID: PMC11972886 DOI: 10.1016/j.ajt.2024.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 11/22/2024] [Accepted: 12/13/2024] [Indexed: 12/20/2024]
Abstract
After skin allotransplantation, intercellular transfer of donor major histocompatibility complex molecules mediated primarily by extracellular vesicles (EVs) released by the allograft is known to contribute to semidirect and indirect activation of alloreactive T cells involved in graft rejection. At the same time, there is ample evidence showing that initiation of adaptive alloimmunity depends on early innate inflammation caused by tissue injury and subsequent activation of myeloid cells (macrophages and dendritic cells) recognizing danger-associated molecular patterns. Among these danger-associated molecular patterns, extracellular adenosine triphosphate plays a key role in innate inflammation by binding to P2X7 receptors (P2X7Rs). Indeed, this process leads to the activation of the Nod-like receptor protein 3 inflammasome and the subsequent production and release of inflammatory cytokines and EVs. This prompted us to evaluate the influence of innate inflammation triggered by adenosine triphosphate-mediated signaling of P2X7Rs on EV release by donor cells after skin transplantation in mice. In this article, we show that inhibition of P2X7R signaling suppresses both EV release and major histocompatibility complex cross-decoration of leukocytes and prolongs skin allograft survival in mice. This study reveals a novel aspect of the role of innate immunity in allotransplantation.
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Affiliation(s)
- Bruno Gonzalez-Nolasco
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Hyshem H Lancia
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Natacha Carnel-Amar
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Xianding Wang
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Aurore Prunevieille
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Loïc Van Dieren
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Alexandre G Lellouch
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Curtis L Cetrulo
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Gilles Benichou
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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5
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Pan T, Li J, Zhu L, Guo H, Wang L, Feng H, Zhao D, Chen G. Establishment of a rat model of pediatric-to-adult kidney transplantation to study the early rapid compensatory growth of the grafts. FASEB J 2025; 39:e70481. [PMID: 40105183 DOI: 10.1096/fj.202402958r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 02/26/2025] [Accepted: 03/12/2025] [Indexed: 03/20/2025]
Abstract
Pediatric donor kidneys show rapid compensatory development in morphology and function after being transplanted into adult recipients. Establishing an animal model that can simulate clinical pediatric-to-adult (P→A) kidney transplantation is important for studying the characteristics and potential mechanisms related to this rapid graft growth. In the P→A group, kidneys harvested from 3- to 4-week-old Sprague-Dawley (SD) rats weighing <50 g were transplanted into adult SD rats (300-400 g). Novel techniques were employed using recipient common iliac vessels for vascular anastomosis and ureter graft drag-in connection to the recipient bladder. As a control group, conventional kidney transplantation was performed between adult SD rats (A→A group). A total of 11 transplants were performed in the P→A group. Eight recipients survived to 28 days without obvious complications and were euthanized for graft harvesting and analysis. Ultrasonography showed that the renal grafts grew significantly faster in the P→A group than in the A→A group during the first 7 days after transplantation, and the size of the renal grafts in the two groups was similar on day 28. Histology revealed significant glomerular enlargement and cell proliferation in the pediatric donor kidneys, with signs of hyperfiltration injury but without podocyte proliferation. Proximal tubular epithelial cells (PTECs) in the P→A group showed significant cell proliferation and hypertrophy. This study has successfully established an animal model in rats with similar characteristics to clinical P→A kidney transplantation, providing a new tool for studying the pathophysiological changes and potential mechanisms of early rapid compensatory growth of the grafts after small pediatric donor kidneys were transplanted into size-mismatched large adult recipients.
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Affiliation(s)
- Tianhui Pan
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junbo Li
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lan Zhu
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Ministry of Public Health, Chinese Academy of Medical Sciences, Wuhan, China
| | - Hui Guo
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Ministry of Public Health, Chinese Academy of Medical Sciences, Wuhan, China
| | - Lu Wang
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Ministry of Public Health, Chinese Academy of Medical Sciences, Wuhan, China
| | - Hao Feng
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Daqiang Zhao
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Ministry of Public Health, Chinese Academy of Medical Sciences, Wuhan, China
| | - Gang Chen
- Institution of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Ministry of Public Health, Chinese Academy of Medical Sciences, Wuhan, China
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Chen S, Zhao Y, Yi W, Zhou X, Wang J, Yang B, Lan P, Chen Z. CD40 induces PIR-A + macrophages to promote chronic allograft rejection. Int Immunopharmacol 2025; 150:114274. [PMID: 39954660 DOI: 10.1016/j.intimp.2025.114274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 01/29/2025] [Accepted: 02/07/2025] [Indexed: 02/17/2025]
Abstract
BACKGROUND Chronic rejection is the leading cause of progressive allograft function decline. Studies have demonstrated that CD40-CD40L-induced paired immunoglobulin-like receptor-A (PIR-A) is the MHC-I receptor necessary for the specific memory response in macrophages of mice with chronic rejection. However, the underlying mechanisms remain unclear. METHODS BALB/c mouse hearts were transplanted into C57BL/6, RelB-/- or LysMCrePirafl/fl mice, and a chronic rejection model was established by injecting CTLA-4-Ig. CD40-CD40L blockade in recipients by injecting anti-CD40L antibody. Allograft survival was monitored and histologically was assessed. Bone marrow-derived macrophages were treated with an anti-CD40 antibody. PIR-A expression was assessed via various methods in vivo and in vitro. Transcription factor expression levels were detected using RNA sequencing. DNA specifically bound to transcription factors was detected using ChIP-seq. RESULTS CD40 and PIR-A were highly expressed and colocalized in macrophage-infiltrating allograft in the mouse model. CD40-CD40L blockade inhibited PIR-A expression and prolonged allograft survival. Conditional deletion of Pira in recipient's macrophages inhibited chronic rejection and promoted long-term allograft acceptance. Mechanistically, CD40 may activate transcription factor NF-κB2 translocation into the nucleus to up-regulate PIR-A expression, promoting chronic rejection of cardiac transplantation. NF-κB2 regulated PIR-A expression by binding to the intergenic region of Pira. CONCLUSIONS Our data suggest that Pira is a potential target to induce long-term allograft tolerance. CD40 may activate transcription factor NF-κB2 translocation into the nucleus to up-regulate PIR-A expression, promoting chronic rejection of cardiac transplantation. The study findings provide novel therapeutic opportunities to promote transplant survival in clinical settings.
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Affiliation(s)
- Shi Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China; Department of Thyroid Surgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuanyuan Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Wang Yi
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xi Zhou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Jingzeng Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Bo Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Peixiang Lan
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
| | - Zhishui Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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Bery AI, Belousova N, Hachem RR, Roux A, Kreisel D. Chronic Lung Allograft Dysfunction: Clinical Manifestations and Immunologic Mechanisms. Transplantation 2025; 109:454-466. [PMID: 39104003 PMCID: PMC11799353 DOI: 10.1097/tp.0000000000005162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/07/2024]
Abstract
The term "chronic lung allograft dysfunction" has emerged to describe the clinical syndrome of progressive, largely irreversible dysfunction of pulmonary allografts. This umbrella term comprises 2 major clinical phenotypes: bronchiolitis obliterans syndrome and restrictive allograft syndrome. Here, we discuss the clinical manifestations, diagnostic challenges, and potential therapeutic avenues to address this major barrier to improved long-term outcomes. In addition, we review the immunologic mechanisms thought to propagate each phenotype of chronic lung allograft dysfunction, discuss the various models used to study this process, describe potential therapeutic targets, and identify key unknowns that must be evaluated by future research strategies.
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Affiliation(s)
- Amit I Bery
- Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Natalia Belousova
- Pneumology, Adult Cystic Fibrosis Center and Lung Transplantation Department, Foch Hospital, Suresnes, France
| | - Ramsey R Hachem
- Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Antoine Roux
- Pneumology, Adult Cystic Fibrosis Center and Lung Transplantation Department, Foch Hospital, Suresnes, France
- Paris Transplant Group, INSERM U 970s, Paris, France
| | - Daniel Kreisel
- Departments of Surgery, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO
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Rabant M, Adam BA, Aubert O, Böhmig GA, Clahsen Van-Groningen M, Cornell LD, de Vries APJ, Huang E, Kozakowski N, Perkowska-Ptasinska A, Riella LV, Rosales IA, Schinstock C, Simmonds N, Thaunat O, Willicombe M. Banff 2022 Kidney Commentary: Reflections and Future Directions. Transplantation 2025; 109:292-299. [PMID: 38886879 DOI: 10.1097/tp.0000000000005112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
In September 2022, in Banff, Alberta, Canada, the XVIth Banff meeting, corresponding to the 30th anniversary of the Banff classification, was held, leading to 2 recent publications. Discussions at the Banff meeting focused on proposing improvements to the Banff process as a whole. In line with this, a unique opportunity was offered to a selected group of 16 representatives from the pathology and transplant nephrology community, experts in the field of kidney transplantation, to review these 2 Banff manuscripts. The aim was to provide an insightful commentary, to gauge any prospective influence the proposed changes may have, and to identify any potential areas for future enhancement within the Banff classification. The group expressed its satisfaction with the incorporation of 2 new entities, namely "microvascular inflammation/injury donor-specific antibodies-negative and C4d negative" and "probable antibody-mediated rejection," into category 2. These changes expand the classification, facilitating the capture of more biopsies and providing an opportunity to explore the clinical implications of these lesions further. However, we found that the Banff classification remains complex, potentially hindering its widespread utilization, even if a degree of complexity may be unavoidable given the intricate pathophysiology of kidney allograft pathology. Addressing the histomorphologic diagnosis of chronic active T cell-mediated rejection (CA TCMR), potentially reconsidering a diagnostic-agnostic approach, as for category 2, to inflammation in interstitial fibrosis and tubular atrophy and chronic active T cell-mediated rejection was also an important objective. Furthermore, we felt a need for more evidence before molecular diagnostics could be routinely integrated and emphasized the need for clinical and histologic context determination and the substantiation of its clinical impact through rigorous clinical trials. Finally, our discussions stressed the ongoing necessity for multidisciplinary decision-making regarding patient care.
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Affiliation(s)
- Marion Rabant
- Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Benjamin A Adam
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Olivier Aubert
- Kidney Transplant Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Georg A Böhmig
- Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Marian Clahsen Van-Groningen
- Department of Pathology and Clinical Bioinformatics, Erasmus MC Transplant Institute, Rotterdam, the Netherlands
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
| | - Lynn D Cornell
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Aiko P J de Vries
- Division of Nephrology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
- Leiden Transplant Center, Leiden University Medical Center, Leiden, the Netherlands
| | - Edmund Huang
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | | | - Leonardo V Riella
- Nephrology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Ivy A Rosales
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Carrie Schinstock
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Naomi Simmonds
- Department of Pathology, Guys and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Olivier Thaunat
- Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France
| | - Michelle Willicombe
- Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom
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9
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Nankivell BJ, Viswanathan S. Early and Late Microvascular Inflammation Have Differing Etiological Causes and Clinical Expression. Transplantation 2025; 109:376-385. [PMID: 39344003 DOI: 10.1097/tp.0000000000005224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
BACKGROUND Microvascular inflammation (MVI) is an important pathological feature of antibody-mediated rejection (AMR). How posttransplant time affects its clinicopathological expression is little understood. METHODS This retrospective, single-center study screened 3398 kidney transplant biopsies and dichotomized 202 MVI ≥ 2 (Banff glomerulitis + peritubular capillaritis ≥ 2) samples by 9-mo median incidence time for comparison. RESULTS The prevalence of MVI ≥ 2 was 12.4% in transplant kidneys, which failed more frequently than propensity-matched normal controls (n = 202; P < 0.001). Epidemiological risk factors for early MVI ≥ 2 were delayed graft function, prior AMR, and circulating donor-specific antibodies (DSAs+). Prior recipient sensitization occurred in 72.3%. Early MVI ≥ 2 was classified AMR in 65.3% and cellular rejection in 34.7%, and demonstrated excellent functional recovery and graft survival comparable to normal control kidneys. Late MVI ≥ 2 was predicted by younger (18 = 29 y) age, female recipient, living-donation, prior methylprednisolone, cyclosporine (versus tacrolimus, levels <5 ng/mL), absent antiproliferative therapy, and DSA+ using multivariable epidemiological modeling. Nonadherence caused 49.5%, with iatrogenic minimization responsible for 47.5%, usually for recipient infection. Late MVI ≥ 2 was because of AMR in 93.1%, and characterized by greater interstitial fibrosis, tubular atrophy, complement degradation split-product 4d (C4d) staining of peritubular capillaries+, endothelial C4d staining of glomerular capillaries+, transplant glomerulopathy and vasculopathy scores, DSA strength, and graft failure than early MVI ≥ 2 or normal transplant kidneys. Death-censored graft survival in 149 unique MVI ≥ 2 kidneys was independently determined by nonadherence, serum creatinine, proteinuria, DSA+, Banff C4d staining of peritubular capillaries+, and chronic interstitial fibrosis scores. MVI score and time lost significance using multivariable Cox regression. CONCLUSIONS The changing expression of MVI ≥ 2 over time is best explained by differences in underimmunosuppression and microvascular injury from AMR impacting allograft function and survival.
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Affiliation(s)
- Brian J Nankivell
- Department of Renal Medicine, Westmead Hospital, Westmead, NSW, Australia
| | - Seethalakshmi Viswanathan
- Department of Tissue Pathology and Diagnostic Oncology, ICPMR, Westmead Hospital, Westmead, NSW, Australia
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10
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Nankivell BJ, Taverniti A, Viswanathan S, Ronquillo J, Carroll R, Sharma A. The relationship of microvascular inflammation with antibody-mediated rejection in kidney transplantation. Am J Transplant 2025; 25:115-126. [PMID: 39084463 DOI: 10.1016/j.ajt.2024.07.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/02/2024]
Abstract
Microvascular inflammation (MVI) is a key diagnostic feature of antibody-mediated rejection (AMR); however, recipients without donor-specific antibodies (DSA) defy etiologic classification using C4d staining of peritubular capillaries (C4dptc) and conventional DSA assignment. We evaluated MVI ≥ 2 (Banff g + ptc ≥ 2) using Banff 2019 AMR (independent of MVI ≥ 2 but including C4dptc) with unconventional endothelial C4d staining of glomerular capillaries (C4dglom) and - arterial endothelium and/or intima (C4dart) using tissue immunoperoxidase, shared-eplet and subthreshold DSA (median fluorescence intensity, [MFI] 100-499), and capillary ultrastructure from 3398 kidney transplant samples for evidence of AMR. MVI ≥ 2 (n = 202 biopsies) from 149 kidneys (12.4% prevalence) correlated with DSA+, C4dptc+, C4dglom+, Banff cg, i, t, ti scores, serum creatinine, proteinuria, and graft failure compared with 202 propensity score matched normal controls. The laboratory reported DSA- MVI ≥ 2 (MFI ≥500) occurred in 34.7%; however, subthreshold (28.6%), eplet-directed (51.4%), and/or misclassified anti-Human leukocyte antigen (HLA) DSA (12.9%) were identified in 67.1% by forensic reanalysis, with vascular C4d+ staining in 67.1%, and endothelial abnormalities in 57.1%, totaling 87.1%. Etiologic analysis attributed 62.9% to AMR (77.8% for MVI with negative reported DSA [DSA- MVI ≥2] with glomerulitis) and pure T cellular rejection in 37.1%. C4dptc-DSA- MVI ≥ 2 was unrecognized AMR in 48.0%. Functional outcomes and graft survival were comparable to normal controls. We concluded that DSA- MVI ≥ 2 frequently signified a mild "borderline" phenotype of AMR which was recognizable using novel serologic and pathological techniques.
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Affiliation(s)
- Brian J Nankivell
- Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia.
| | - Anne Taverniti
- New South Wales Transplantation and Immunogenetics, Australian Red Cross, LifeBlood, New South Wales, Australia
| | | | - John Ronquillo
- Tissue Pathology and Diagnostic Oncology, ICPMR, Sydney, Australia
| | - Robert Carroll
- New South Wales Transplantation and Immunogenetics, Australian Red Cross, LifeBlood, New South Wales, Australia
| | - Ankit Sharma
- Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia
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11
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Yun IH, Yang J. Mechanisms of allorecognition and xenorecognition in transplantation. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:273-293. [PMID: 39743230 PMCID: PMC11732770 DOI: 10.4285/ctr.24.0056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/29/2024] [Accepted: 11/29/2024] [Indexed: 01/04/2025]
Abstract
Foreign antigen recognition is the ability of immune cells to distinguish self from nonself, which is crucial for immune responses in both invertebrates and vertebrates. In vertebrates, T cells play a pivotal role in graft rejection by recognizing alloantigens presented by antigen-presenting cells through direct, indirect, or semidirect pathways. B cells also significantly contribute to the indirect presentation of antigens to T cells. Innate immune cells, such as dendritic cells, identify pathogen- or danger-associated molecular patterns through pattern recognition receptors, thereby facilitating effective antigen presentation to T cells. Recent studies have shown that innate immune cells, including macrophages and NK cells, can recognize allogeneic or xenogeneic antigens using immune receptors like CD47 or activating NK receptors, instead of pattern recognition receptors. Additionally, macrophages and NK cells are capable of exhibiting memory responses to alloantigens, although these responses are shorter than those of adaptive memory. T cells also recognize xenoantigens through either direct or indirect presentation. Notably, macrophages and NK cells can directly recognize xenoantigens via surface immune receptors in an antibody-independent manner, or they can be activated in an antibody-dependent manner. Advances in our understanding of the recognition mechanisms of adaptive and innate immunity against allogeneic and xenogeneic antigens may improve our understanding of graft rejection.
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Affiliation(s)
- Il Hee Yun
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Jaeseok Yang
- The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
- Division of Nephrology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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12
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Yang J, Cui S, Shao B, Zhao Y, Wang Z, Liu Q, Zhang Y, Yang D. ScRNA-seq reveals trained immunity-engaged Th17 cell activation against Edwardsiella piscicida-induced intestinal inflammation in teleost. Microbiol Res 2024; 289:127912. [PMID: 39326350 DOI: 10.1016/j.micres.2024.127912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/19/2024] [Accepted: 09/13/2024] [Indexed: 09/28/2024]
Abstract
Mucosal immunity typically involves innate and adaptive immune cells, while the cellular mechanism of teleost's intestinal immune cells that engages gut homeostasis against bacterial infection remains largely unknown. Taking advantage of the enteric fish pathogen (Edwardsiella piscicida) infection-induced intestinal inflammation in turbot (Scophthalmus maximus), we find that β-glucan training could mitigate the bacterial infection-induced intestinal inflammation. Through single-cell transcriptome profiling and cellular function analysis, we identify that E. piscicida infection could tune down the activation of intestinal Th17 cells, while β-glucan-training could preserve the potential to amplify and restore the function of intestinal Th17 cells. Moreover, through pharmacological inhibitor treatment, we identify that Th17 cells are essential for ameliorating bacterial infection-induced intestinal inflammation in teleost. Taken together, these results suggest a new concept of trained immunity activation to regulate the intestinal Th17 cells' function, which might contribute to better developing strategies for maintaining gut homeostasis against bacterial infection.
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Affiliation(s)
- Jin Yang
- State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China
| | - Shu Cui
- State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China
| | - Boning Shao
- State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China
| | - Yanbo Zhao
- State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China
| | - Zhuang Wang
- State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China
| | - Qin Liu
- State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China; Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China; Shanghai Engineering Research Center of Maricultured Animal Vaccines, Shanghai 200237, China
| | - Yuanxing Zhang
- State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China; Shanghai Engineering Research Center of Maricultured Animal Vaccines, Shanghai 200237, China
| | - Dahai Yang
- State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China; Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, China; Shanghai Engineering Research Center of Maricultured Animal Vaccines, Shanghai 200237, China.
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13
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Robertson H, Kim HJ, Li J, Robertson N, Robertson P, Jimenez-Vera E, Ameen F, Tran A, Trinh K, O'Connell PJ, Yang JYH, Rogers NM, Patrick E. Decoding the hallmarks of allograft dysfunction with a comprehensive pan-organ transcriptomic atlas. Nat Med 2024; 30:3748-3757. [PMID: 38890530 PMCID: PMC11645273 DOI: 10.1038/s41591-024-03030-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 04/29/2024] [Indexed: 06/20/2024]
Abstract
The pathogenesis of allograft (dys)function has been increasingly studied using 'omics'-based technologies, but the focus on individual organs has created knowledge gaps that neither unify nor distinguish pathological mechanisms across allografts. Here we present a comprehensive study of human pan-organ allograft dysfunction, analyzing 150 datasets with more than 12,000 samples across four commonly transplanted solid organs (heart, lung, liver and kidney, n = 1,160, 1,241, 1,216 and 8,853 samples, respectively) that we leveraged to explore transcriptomic differences among allograft dysfunction (delayed graft function, acute rejection and fibrosis), tolerance and stable graft function. We identified genes that correlated robustly with allograft dysfunction across heart, lung, liver and kidney transplantation. Furthermore, we developed a transfer learning omics prediction framework that, by borrowing information across organs, demonstrated superior classifications compared to models trained on single organs. These findings were validated using a single-center prospective kidney transplant cohort study (a collective 329 samples across two timepoints), providing insights supporting the potential clinical utility of our approach. Our study establishes the capacity for machine learning models to learn across organs and presents a transcriptomic transplant resource that can be employed to develop pan-organ biomarkers of allograft dysfunction.
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Affiliation(s)
- Harry Robertson
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
| | - Hani Jieun Kim
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, New South Wales, Australia
- Kinghorn Cancer Centre and Cancer Research Theme, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Jennifer Li
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Nicholas Robertson
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Laboratory of Data Discovery for Health Limited (D24H), Science Park, Hong Kong SAR, China
| | - Paul Robertson
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Elvira Jimenez-Vera
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Farhan Ameen
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
| | - Andy Tran
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
| | - Katie Trinh
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Philip J O'Connell
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - Jean Y H Yang
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Laboratory of Data Discovery for Health Limited (D24H), Science Park, Hong Kong SAR, China
| | - Natasha M Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - Ellis Patrick
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia.
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia.
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia.
- Laboratory of Data Discovery for Health Limited (D24H), Science Park, Hong Kong SAR, China.
- Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
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14
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Yosri M, Dokhan M, Aboagye E, Al Moussawy M, Abdelsamed HA. Mechanisms governing bystander activation of T cells. Front Immunol 2024; 15:1465889. [PMID: 39669576 PMCID: PMC11635090 DOI: 10.3389/fimmu.2024.1465889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 10/31/2024] [Indexed: 12/14/2024] Open
Abstract
The immune system is endowed with the capacity to distinguish between self and non-self, so-called immune tolerance or "consciousness of the immune system." This type of awareness is designed to achieve host protection by eliminating cells expressing a wide range of non-self antigens including microbial-derived peptides. Such a successful immune response is associated with the secretion of a whole spectrum of soluble mediators, e.g., cytokines and chemokines, which not only contribute to the clearance of infected host cells but also activate T cells that are not specific to the original cognate antigen. This kind of non-specific T-cell activation is called "bystander activation." Although it is well-established that this phenomenon is cytokine-dependent, there is evidence in the literature showing the involvement of peptide/MHC recognition depending on the type of T-cell subset (naive vs. memory). Here, we will summarize our current understanding of the mechanism(s) of bystander T-cell activation as well as its biological significance in a wide range of diseases including microbial infections, cancer, auto- and alloimmunity, and chronic inflammatory diseases such as atherosclerosis.
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Affiliation(s)
- Mohammed Yosri
- The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt
| | - Mohamed Dokhan
- Immunology Center of Georgia (IMMCG), Medical College of Georgia (MCG), Augusta University, Augusta, GA, United States
| | - Elizabeth Aboagye
- Immunology Center of Georgia (IMMCG), Medical College of Georgia (MCG), Augusta University, Augusta, GA, United States
| | - Mouhamad Al Moussawy
- Starzl Transplantation Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Hossam A. Abdelsamed
- Immunology Center of Georgia (IMMCG), Medical College of Georgia (MCG), Augusta University, Augusta, GA, United States
- Department of Physiology, Augusta University, Augusta, GA, United States
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15
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Benning L, Bestard O. Shedding Light on Microvascular Inflammation: Understanding Outcomes, But What Sparks the Flame? Transpl Int 2024; 37:14032. [PMID: 39659965 PMCID: PMC11628253 DOI: 10.3389/ti.2024.14032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024]
Affiliation(s)
- Louise Benning
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Oriol Bestard
- Department of Nephrology and Kidney Transplantation, Vall d’Hebrón University Hospital, Barcelona, Spain
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16
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Fiske KL, Brigleb PH, Sanchez LM, Hinterleitner R, Taylor GM, Dermody TS. Strain-specific differences in reovirus infection of murine macrophages segregate with polymorphisms in viral outer-capsid protein σ3. J Virol 2024; 98:e0114724. [PMID: 39431846 PMCID: PMC11575339 DOI: 10.1128/jvi.01147-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 09/22/2024] [Indexed: 10/22/2024] Open
Abstract
Mammalian orthoreovirus (reovirus) strains type 1 Lang (T1L) and type 3 Dearing-RV (T3D-RV) infect the intestine in mice but differ in the induction of inflammatory responses. T1L infection is associated with the blockade of oral immunological tolerance to newly introduced dietary antigens, whereas T3D-RV is not. T1L infection leads to an increase in infiltrating phagocytes, including macrophages, in gut-associated lymphoid tissues that are not observed in T3D-RV infection. However, the function of macrophages in reovirus intestinal infection is unknown. Using cells sorted from infected intestinal tissue and primary cultures of bone-marrow-derived macrophages (BMDMs), we discovered that T1L infects macrophages more efficiently than T3D-RV. Analysis of T1L × T3D-RV reassortant viruses revealed that the viral S4 gene segment, which encodes outer-capsid protein σ3, is responsible for strain-specific differences in infection of BMDMs. Differences in the binding of T1L and T3D-RV to BMDMs also segregated with the σ3-encoding S4 gene. Paired immunoglobulin-like receptor B (PirB), which serves as a receptor for reovirus, is expressed on macrophages and engages σ3. We found that PirB-specific antibody blocks T1L binding to BMDMs and that T1L binding to PirB-/- BMDMs is significantly diminished. Collectively, our data suggest that reovirus T1L infection of macrophages is dependent on engagement of PirB by viral outer-capsid protein σ3. These findings raise the possibility that macrophages function in the innate immune response to reovirus infection that blocks immunological tolerance to new food antigens.IMPORTANCEMammalian orthoreovirus (reovirus) infects humans throughout their lifespan and has been linked to celiac disease (CeD). CeD is caused by a loss of oral immunological tolerance (LOT) to dietary gluten and leads to intestinal inflammation following gluten ingestion, which worsens with prolonged exposure and can cause malnutrition. There are limited treatment options for CeD. While there are genetic risk factors associated with the illness, triggers for disease onset are not completely understood. Enteric viruses, including reovirus, have been linked to CeD induction. We found that a reovirus strain associated with oral immunological tolerance blockade infects macrophages by virtue of its capacity to bind macrophage receptor PirB. These data contribute to an understanding of the innate immune response elicited by reovirus, which may shed light on how viruses trigger LOT and inform the development of CeD vaccines and therapeutic agents.
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Affiliation(s)
- Kay L. Fiske
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Institute of Infection, Inflammation, and Immunity, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Pamela H. Brigleb
- Institute of Infection, Inflammation, and Immunity, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Luzmariel Medina Sanchez
- Institute of Infection, Inflammation, and Immunity, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Graduate Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Reinhard Hinterleitner
- Institute of Infection, Inflammation, and Immunity, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Gwen M. Taylor
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Institute of Infection, Inflammation, and Immunity, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Terence S. Dermody
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Institute of Infection, Inflammation, and Immunity, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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17
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Charmetant X, Pettigrew GJ, Thaunat O. Allorecognition Unveiled: Integrating Recent Breakthroughs Into the Current Paradigm. Transpl Int 2024; 37:13523. [PMID: 39588197 PMCID: PMC11586167 DOI: 10.3389/ti.2024.13523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 10/29/2024] [Indexed: 11/27/2024]
Abstract
In transplantation, genetic differences between donor and recipient trigger immune responses that cause graft rejection. Allorecognition, the process by which the immune system discriminates allogeneic grafts, targets major histocompatibility complex (MHC) and minor histocompatibility antigens. Historically, it was believed that allorecognition was solely mediated by the recipient's adaptive immune system recognizing donor-specific alloantigens. However, recent research has shown significant roles for innate immune components, such as lymphoid and myeloid cells, which are sometimes triggered by the mere absence of a self-protein in the graft. This review integrates recent breakthroughs into the current allorecognition paradigm based on the well-established direct and indirect pathways, emphasizing the semi-direct pathway where recipient antigen-presenting cells (APCs) acquire donor MHC molecules, and the inverted direct pathway where donor CD4+ T cells within the graft activate recipient B cells to produce donor-specific antibodies (DSAs). The review also explores the role of natural killer (NK) cells in both promoting and inhibiting graft rejection, highlighting their dual role in innate allorecognition. Additionally, it discusses the emerging understanding of myeloid cell-mediated allorecognition and its implications for initiating adaptive immune responses. These insights aim to provide a more comprehensive understanding of allorecognition, potentially leading to improved transplant outcomes.
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Affiliation(s)
- Xavier Charmetant
- Centre International de Recherche en Infectiologie, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University Lyon, Lyon, France
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
- Lyon-Est Faculty of Medicine, Claude Bernard University (Lyon 1), Villeurbanne, France
| | - Gavin J. Pettigrew
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Olivier Thaunat
- Centre International de Recherche en Infectiologie, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University Lyon, Lyon, France
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
- Lyon-Est Faculty of Medicine, Claude Bernard University (Lyon 1), Villeurbanne, France
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18
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Jonkman I, Jacobs MME, Negishi Y, Yanginlar C, Martens JHA, Baltissen M, Vermeulen M, van den Hoogen MWF, Baas M, van der Vlag J, Fayad ZA, Teunissen AJP, Madsen JC, Ochando J, Joosten LAB, Netea MG, Mulder WJM, Mhlanga MM, Hilbrands LB, Rother N, Duivenvoorden R. Trained immunity suppression determines kidney allograft survival. Am J Transplant 2024; 24:2022-2033. [PMID: 39147201 PMCID: PMC11789421 DOI: 10.1016/j.ajt.2024.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 08/02/2024] [Accepted: 08/08/2024] [Indexed: 08/17/2024]
Abstract
The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.
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Affiliation(s)
- Inge Jonkman
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Maaike M E Jacobs
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Yutaka Negishi
- Department of Molecular Biology, Faculty of Science, Oncode Institute, Radboud University Nijmegen, Nijmegen, The Netherlands; Department of Cell Biology, Faculty of Science, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Cansu Yanginlar
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joost H A Martens
- Department of Molecular Biology, Faculty of Science, Oncode Institute, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Marijke Baltissen
- Department of Molecular Biology, Faculty of Science, Oncode Institute, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Michiel Vermeulen
- Department of Molecular Biology, Faculty of Science, Oncode Institute, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Martijn W F van den Hoogen
- Department of Internal Medicine, Erasmus Medical Center Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Marije Baas
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Johan van der Vlag
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Zahi A Fayad
- Department of Radiology, Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Abraham J P Teunissen
- Department of Radiology, Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Joren C Madsen
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA; Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jordi Ochando
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Transplant Immunology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Medical Genetics, University of Medicine and Pharmacy, Iuliu Haţieganu, Cluj-Napoca, Romania
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Willem J M Mulder
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Biomedical Engineering and Institute for Complex Molecular Systems, Laboratory of Chemical Biology, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Musa M Mhlanga
- Department of Molecular Biology, Faculty of Science, Oncode Institute, Radboud University Nijmegen, Nijmegen, The Netherlands; Department of Cell Biology, Faculty of Science, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Luuk B Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nils Rother
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Raphaël Duivenvoorden
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Radiology, Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
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19
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Owen MC, Kopecky BJ. Targeting Macrophages in Organ Transplantation: A Step Toward Personalized Medicine. Transplantation 2024; 108:2045-2056. [PMID: 38467591 PMCID: PMC11390981 DOI: 10.1097/tp.0000000000004978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
Organ transplantation remains the most optimal strategy for patients with end-stage organ failure. However, prevailing methods of immunosuppression are marred by adverse side effects, and allograft rejection remains common. It is imperative to identify and comprehensively characterize the cell types involved in allograft rejection, and develop therapies with greater specificity. There is increasing recognition that processes mediating allograft rejection are the result of interactions between innate and adaptive immune cells. Macrophages are heterogeneous innate immune cells with diverse functions that contribute to ischemia-reperfusion injury, acute rejection, and chronic rejection. Macrophages are inflammatory cells capable of innate allorecognition that strengthen their responses to secondary exposures over time via "trained immunity." However, macrophages also adopt immunoregulatory phenotypes and may promote allograft tolerance. In this review, we discuss the roles of macrophages in rejection and tolerance, and detail how macrophage plasticity and polarization influence transplantation outcomes. A comprehensive understanding of macrophages in transplant will guide future personalized approaches to therapies aimed at facilitating tolerance or mitigating the rejection process.
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Affiliation(s)
- Macee C Owen
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MI
| | - Benjamin J Kopecky
- Division of Cardiology, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MI
- Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO
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20
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Xu W, Liu AX, Liu KH, Zhang S, Gong ZH, Xiao WJ. l-Theanine Alleviates Ulcerative Colitis by Regulating Colon Immunity via the Gut Microbiota in an MHC-II-Dependent Manner. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:19852-19868. [PMID: 39197065 DOI: 10.1021/acs.jafc.4c04379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2024]
Abstract
Alterations to the gut microbiota are associated with ulcerative colitis (UC), whereas restoration of normobiosis can effectively alleviate UC. l-Theanine has been shown to reshape the gut microbiota and regulate gut immunity. To investigate the mechanisms by which l-theanine alleviates UC, we used l-theanine and l-theanine fecal microbiota solution to treat UC mice. In this study, we used l-theanine and l-theanine fecal microbiota solution to treat UC mice to explore the mechanism by which l-theanine alleviates UC. By reducing inflammation in the colon, we demonstrated that l-theanine alleviates symptoms of UC. Meanwhile, l-theanine can improve the abundance of microbiota related to short-chain fatty acid, bile acid, and tryptophan production. Single-cell sequencing results indicated that l-theanine-mediated suppression of UC was associated with immune cell changes, especially regarding macrophages and T and B cells, and validated the immune cell responses to the gut microbiota. Further, flow cytometry results showed that the ability of dendritic cells, macrophages, and monocytes to present microbiota antigens to colonic T cells in an MHC-II-dependent manner was reduced after treating normal mouse fecal donors with l-theanine. These results demonstrate that l-theanine modulates colon adaptive and innate immunity by regulating the gut microbiota in an MHC-II-dependent manner, thereby alleviating UC.
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Affiliation(s)
- Wei Xu
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha 410128, Hunan, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, Hunan, China
| | - Ao-Xiang Liu
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha 410128, Hunan, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, Hunan, China
| | - Ke-Hong Liu
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha 410128, Hunan, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, Hunan, China
| | - Sheng Zhang
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha 410128, Hunan, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, Hunan, China
- Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Changsha 410128, Hunan, China
| | - Zhi-Hua Gong
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha 410128, Hunan, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, Hunan, China
- Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Changsha 410128, Hunan, China
| | - Wen-Jun Xiao
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha 410128, Hunan, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, Hunan, China
- Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Changsha 410128, Hunan, China
- Key Laboratory for Evaluation and Utilization of Gene Resources of Horticultural Crops, Ministry of Agriculture and Rural Affairs of China, Hunan Agricultural University, Changsha 410128, Hunan, China
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21
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Wang HY, Chen JY, Li Y, Zhang X, Liu X, Lu Y, He H, Li Y, Chen H, Liu Q, Huang Y, Jia Z, Li S, Zhang Y, Han S, Jiang S, Yang M, Zhang Y, Zhou L, Tan F, Ji Q, Meng L, Wang R, Liu Y, Liu K, Wang Q, Seim I, Zou J, Fan G, Liu S, Shao C. Single-cell RNA sequencing illuminates the ontogeny, conservation and diversification of cartilaginous and bony fish lymphocytes. Nat Commun 2024; 15:7627. [PMID: 39227568 PMCID: PMC11372145 DOI: 10.1038/s41467-024-51761-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 08/16/2024] [Indexed: 09/05/2024] Open
Abstract
Elucidating cellular architecture and cell-type evolution across species is central to understanding immune system function and susceptibility to disease. Adaptive immunity is a shared trait of the common ancestor of cartilaginous and bony fishes. However, evolutionary features of lymphocytes in these two jawed vertebrates remain unclear. Here, we present a single-cell RNA sequencing atlas of immune cells from cartilaginous (white-spotted bamboo shark) and bony (zebrafish and Chinese tongue sole) fishes. Cross-species comparisons show that the same cell types across different species exhibit similar transcriptional profiles. In the bamboo shark, we identify a phagocytic B cell population expressing several pattern recognition receptors, as well as a T cell sub-cluster co-expressing both T and B cell markers. In contrast to a division by function in the bony fishes, we show close linkage and poor functional specialization among lymphocytes in the cartilaginous fish. Our cross-species single-cell comparison presents a resource for uncovering the origin and evolution of the gnathostome immune system.
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Affiliation(s)
- Hong-Yan Wang
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Jian-Yang Chen
- BGI Research, Qingdao, 266555, China
- Qingdao Key Laboratory of Marine Genomics, BGI Research, Qingdao, 266555, Shandong, China
| | - Yanan Li
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, 201306, China
| | - Xianghui Zhang
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Xiang Liu
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
- Qingdao-Europe Advanced Institute for Life Sciences, BGI Research, Qingdao, 266555, China
| | - Yifang Lu
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Hang He
- BGI Research, Qingdao, 266555, China
- Qingdao Key Laboratory of Marine Genomics, BGI Research, Qingdao, 266555, Shandong, China
| | - Yubang Li
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Hongxi Chen
- BGI Research, Qingdao, 266555, China
- Qingdao Key Laboratory of Marine Genomics, BGI Research, Qingdao, 266555, Shandong, China
| | - Qun Liu
- BGI Research, Qingdao, 266555, China
- Qingdao Key Laboratory of Marine Genomics, BGI Research, Qingdao, 266555, Shandong, China
| | - Yingyi Huang
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Zhao Jia
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China
| | - Shuo Li
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Yangqing Zhang
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Shenglei Han
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Shuhong Jiang
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Mingming Yang
- BGI Research, Qingdao, 266555, China
- Qingdao Key Laboratory of Marine Genomics, BGI Research, Qingdao, 266555, Shandong, China
| | - Yingying Zhang
- BGI Research, Qingdao, 266555, China
- Qingdao Key Laboratory of Marine Genomics, BGI Research, Qingdao, 266555, Shandong, China
| | - Li Zhou
- BGI Research, Qingdao, 266555, China
- Qingdao Key Laboratory of Marine Genomics, BGI Research, Qingdao, 266555, Shandong, China
| | - Fujian Tan
- BGI Research, Qingdao, 266555, China
- Qingdao Key Laboratory of Marine Genomics, BGI Research, Qingdao, 266555, Shandong, China
| | | | - Liang Meng
- BGI Research, Qingdao, 266555, China
- Qingdao Key Laboratory of Marine Genomics, BGI Research, Qingdao, 266555, Shandong, China
| | - Rui Wang
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Yuyan Liu
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Kaiqiang Liu
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Qian Wang
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China
| | - Inge Seim
- Integrative Biology Laboratory, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, 4000, Australia
| | - Jun Zou
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, 201306, China
| | - Guangyi Fan
- BGI Research, Qingdao, 266555, China
- Qingdao Key Laboratory of Marine Genomics, BGI Research, Qingdao, 266555, Shandong, China
- BGI Research, Shenzhen, 518083, China
| | | | - Changwei Shao
- State Key Laboratory of Mariculture Biobreeding and Sustainable Goods, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, Shandong, 266071, China.
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237, China.
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22
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Perkins GB, Zuiani JD, Coates PT. The innate immune cells at the heart of kidney allograft rejection. Kidney Int 2024; 106:348-350. [PMID: 38754734 DOI: 10.1016/j.kint.2024.03.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 03/27/2024] [Indexed: 05/18/2024]
Affiliation(s)
- Griffith B Perkins
- Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia, Australia; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
| | - James D Zuiani
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
| | - P Toby Coates
- Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia, Australia; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
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23
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Wei C, Huang Q, Zeng F, Ma L, Bai X, Zhu X, Gao H, Qi X. Cyclic guanosine monophosphate-adenosine monophosphate synthetase/stimulator of interferon genes signaling aggravated corneal allograft rejection through neutrophil extracellular traps. Am J Transplant 2024; 24:1583-1596. [PMID: 38648890 DOI: 10.1016/j.ajt.2024.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 04/13/2024] [Accepted: 04/16/2024] [Indexed: 04/25/2024]
Abstract
The activation of innate immunity following transplantation has been identified as a crucial factor in allograft inflammation and rejection. However, the role of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signaling-mediated innate immunity in the pathogenesis of allograft rejection remains unclear. Utilizing a well-established murine model of corneal transplantation, we demonstrated increased expression of cGAS and STING in rejected-corneal allografts compared with syngeneic (Syn) and normal (Nor) corneas, along with significant activation of the cGAS/STING pathway, as evidenced by the enhanced phosphorylation of TANK-binding kinase 1and interferon regulatory factor 3. Pharmacological and genetic inhibition of cGAS/STING signaling markedly delayed corneal transplantation rejection, resulting in prolonged survival time and reduced inflammatory infiltration. Furthermore, we observed an increase in the formation of neutrophil extracellular traps (NETs) in rejected allografts, and the inhibition of NET formation through targeting peptidylarginine deiminase 4 and DNase I treatment significantly alleviated immune rejection and reduced cGAS/STING signaling activity. Conversely, subconjunctival injection of NETs accelerated corneal transplantation rejection and enhanced the activation of the cGAS/STING pathway. Collectively, these findings demonstrate that NETs contribute to the exacerbation of allograft rejection via cGAS/STING signaling, highlighting the targeting of the NETs/cGAS/STING signaling pathway as a potential strategy for prolonging allograft survival.
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Affiliation(s)
- Chao Wei
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Shandong First Medical University, Qingdao, Shandong, China
| | - Qing Huang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Shandong First Medical University, Qingdao, Shandong, China
| | - Fanxing Zeng
- Refractive Surgery Center, Guangzhou Huangpu Aier Eye Hospital, Guangzhou, Guangdong, China
| | - Li Ma
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Shandong First Medical University, Qingdao, Shandong, China
| | - Xiaofei Bai
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Shandong First Medical University, Qingdao, Shandong, China
| | - Xuejing Zhu
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Medical Department of Qingdao University, Qingdao, Shandong, China
| | - Hua Gao
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Eye Institute of Shandong First Medical University, School of Ophthalmology, Shandong First Medical University, Jinan, Shandong, China
| | - Xiaolin Qi
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Medical Department of Qingdao University, Qingdao, Shandong, China.
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24
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Saha I, Chawla AS, Oliveira APBN, Elfers EE, Warrick K, Meibers HE, Jain VG, Hagan T, Katz JD, Pasare C. Alloreactive memory CD4 T cells promote transplant rejection by engaging DCs to induce innate inflammation and CD8 T cell priming. Proc Natl Acad Sci U S A 2024; 121:e2401658121. [PMID: 39136987 PMCID: PMC11348247 DOI: 10.1073/pnas.2401658121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 07/10/2024] [Indexed: 08/15/2024] Open
Abstract
Alloreactive memory T cells have been implicated as central drivers of transplant rejection. Perplexingly, innate cytokines, such as IL-6, IL-1β, and IL-12, are also associated with rejection of organ transplants. However, the pathways of innate immune activation in allogeneic transplantation are unclear. While the role of microbial and cell death products has been previously described, we identified alloreactive memory CD4 T cells as the primary triggers of innate inflammation. Memory CD4 T cells engaged MHC II-mismatched dendritic cells (DCs), leading to the production of innate inflammatory cytokines. This innate inflammation was independent of several pattern recognition receptors and was primarily driven by TNF superfamily ligands expressed by alloreactive memory CD4 T cells. Blocking of CD40L and TNFα resulted in dampened inflammation, and mice genetically deficient in these molecules exhibited prolonged survival of cardiac allografts. Furthermore, myeloid cell and CD8 T cell infiltration into cardiac transplants was compromised in both CD40L- and TNFα-deficient recipients. Strikingly, we found that priming of naive alloreactive CD8 T cells was dependent on licensing of DCs by memory CD4 T cells. This study unravels the key mechanisms by which alloreactive memory CD4 T cells contribute to destructive pathology and transplant rejection.
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Affiliation(s)
- Irene Saha
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
- Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
| | - Amanpreet Singh Chawla
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
- Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
| | - Ana Paula B. N. Oliveira
- Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
| | - Eileen E. Elfers
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
| | - Kathrynne Warrick
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH45220
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH45229
| | - Hannah E. Meibers
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
- Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH45220
| | - Viral G. Jain
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Thomas Hagan
- Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH45220
| | - Jonathan D. Katz
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH45220
| | - Chandrashekhar Pasare
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
- Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH45229
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH45220
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25
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Thaunat O. Natural killer cell-mediated innate microvascular rejection. Nat Rev Nephrol 2024; 20:489-490. [PMID: 38898355 DOI: 10.1038/s41581-024-00862-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Affiliation(s)
- Olivier Thaunat
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, Lyon, France.
- Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, Lyon, France.
- Claude Bernard University (Lyon 1), Villeurbanne, France.
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26
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Randhawa PS. Caveats in Interpretation of Molecular Diagnostics in Heart Allografts. Transplantation 2024; 108:1472-1475. [PMID: 38294835 DOI: 10.1097/tp.0000000000004895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2024]
Abstract
Histologic separation of injury, T cell-mediated rejection, or antibody-mediated rejection in allograft heart biopsies is difficult. A critical review of publications was performed to evaluate the caveats of using molecular diagnostics (MDX) to distinguish between these entities. Typically, only 1 to 2 fragments of unknown histologic appearance are evaluated. Archetype and molecular classifier analyses use gene lists derived from histologic labels and associated reproducibility issues influence the accuracy of the derived MDX classes. Archetypes A1, A2, and A3 archetypes created by bioinformatics were renamed no rejection, T cell-mediated rejection, and antibody-mediated rejection despite as little as 40% concordance with histologic diagnoses and overlapping archetype scores. Additional archetypes S4 and minor injury were created using arbitrary cutoffs based on visual examination of principal component analysis plots. Therapeutic implications of the numerous discrepancies with histology remain unexplored. Many MDX-derived observations are ambiguous and open to alternate logical explanations. Better molecular methods and more rigorous validation studies are needed to advance the field. Ideally, these methods should analyze all available biopsy fragments to minimize sampling issues. It is also desirable to incorporate spatial transcriptomics into the workflow, so that gene expression data can be directly compared with the underlying histology lesions.
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Affiliation(s)
- Parmjeet S Randhawa
- Department of Pathology, The Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
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Chen S, Yi W, Zhou H, Jiang H, Lan P, Chen Z. FOS+ Macrophages Promote Chronic Rejection of Cardiac Transplantation. EXP CLIN TRANSPLANT 2024; 22:540-550. [PMID: 39223812 DOI: 10.6002/ect.2024.0019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
OBJECTIVES Chronic rejection remains the leading cause of progressive decline in graft function. Accumulating evidence indicates that macrophages participate in chronic rejection dependent on CD40-CD40L. The FOS family members are critical in inflammatory and immune responses. However, the mechanisms underlying the role of FOS family members in chronic rejection remain unclear. In this study, we aimed to elucidate the role and underlying mechanisms of FOS-positive macrophages regulated by CD40 that mediate chronic allograft rejection. MATERIALS AND METHODS We downloaded publicly accessible chronic rejection kidney transplant single-cell sequencing datasets from the gene expression omnibus database. Differentially expressed genes between the CD40hi and CD40low macrophage chronic rejection groups were analyzed. We established a chronic rejection mouse model by using CTLA-4-Ig. We treated bone marrow-derived macrophages with an anti-CD40 antibody. We assessed expression of the FOS family by flow cytometry, real-time quantitative polymerase chain reaction, Western blotting, and immunofluorescence. We identified altered signaling pathways by using RNA sequencing analysis. We detected DNA specifically bound to transcription factors by using ChIP-sequencing, with detection of the degree of graft fibrosis and survival. RESULTS FOS was highly expressed on CD40hi macrophages in patients with chronic transplantrejection. Mechanistically, we showed that CD40 activated NF-κB2 translocation into the nucleus to upregulate c-Fos and FosB expression, thus promoting chronic rejection of cardiac transplant.We showed thatNF-κB2 regulated c-Fos and FosB expression by binding to the c-fos and fosb promoter regions. Inhibition of c-Fos/activator protein-1 decreased graft fibrosis and prolonged graft survival. CONCLUSIONS CD40 may activate transcription factor NF-κB2 translocation into the nucleus of macrophages to upregulate c-Fos and FosB expression, thus promoting chronic rejection of cardiac transplant. Inhibition of c-Fos/activator protein-1 decreased grafts fibrosis and prolonged graft survival.
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Affiliation(s)
- Shi Chen
- >From the Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China Key Laboratory of Organ Transplantation, Ministry of Education; the NHC Key Laboratory of Organ Transplantation; and the Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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Palvair J, Farhat I, Chaintreuil M, Dal Zuffo L, Messager L, Tinel C, Lamarthée B. The Potential Role of the Leucocyte Immunoglobulin-Like Receptors in Kidney Transplant Rejection: A Mini Review. Transpl Int 2024; 37:12995. [PMID: 39010891 PMCID: PMC11247310 DOI: 10.3389/ti.2024.12995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/12/2024] [Indexed: 07/17/2024]
Abstract
Antibody-mediated rejection (ABMR) remains one of the main causes of long-term graft failure after kidney transplantation, despite the development of powerful immunosuppressive therapy. A detailed understanding of the complex interaction between recipient-derived immune cells and the allograft is therefore essential. Until recently, ABMR mechanisms were thought to be solely caused by adaptive immunity, namely, by anti-human leucocyte antigen (HLA) donor-specific antibody. However recent reports support other and/or additive mechanisms, designating monocytes/macrophages as innate immune contributors of ABMR histological lesions. In particular, in mouse models of experimental allograft rejection, monocytes/macrophages are readily able to discriminate non-self via paired immunoglobulin receptors (PIRs) and thus accelerate rejection. The human orthologs of PIRs are leukocyte immunoglobulin-like receptors (LILRs). Among those, LILRB3 has recently been reported as a potential binder of HLA class I molecules, shedding new light on LILRB3 potential as a myeloid mediator of allograft rejection. In this issue, we review the current data on the role of LILRB3 and discuss the potential mechanisms of its biological functions.
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Affiliation(s)
- Jovanne Palvair
- Université de Franche-Comté, EFS, INSERM, UMR RIGHT, Besançon, France
| | - Imane Farhat
- Université de Franche-Comté, EFS, INSERM, UMR RIGHT, Besançon, France
- Centre Hospitalier Universitaire de Dijon, Service de Néphrologie et Transplantation Rénale, Université de Bourgogne, Dijon, France
| | - Mélanie Chaintreuil
- Centre Hospitalier Universitaire de Dijon, Service de Néphrologie et Transplantation Rénale, Université de Bourgogne, Dijon, France
| | | | - Lennie Messager
- Université de Franche-Comté, EFS, INSERM, UMR RIGHT, Besançon, France
| | - Claire Tinel
- Université de Franche-Comté, EFS, INSERM, UMR RIGHT, Besançon, France
- Centre Hospitalier Universitaire de Dijon, Service de Néphrologie et Transplantation Rénale, Université de Bourgogne, Dijon, France
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Gui Z, Al Moussawy M, Sanders SM, Abou-Daya KI. Innate Allorecognition in Transplantation: Ancient Mechanisms With Modern Impact. Transplantation 2024; 108:1524-1531. [PMID: 38049941 PMCID: PMC11188633 DOI: 10.1097/tp.0000000000004847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/15/2023] [Accepted: 09/19/2023] [Indexed: 12/06/2023]
Abstract
Through the effective targeting of the adaptive immune system, solid organ transplantation became a life-saving therapy for organ failure. However, beyond 1 y of transplantation, there is little improvement in transplant outcomes. The adaptive immune response requires the activation of the innate immune system. There are no modalities for the specific targeting of the innate immune system involvement in transplant rejection. However, the recent discovery of innate allorecognition and innate immune memory presents novel targets in transplantation that will increase our understanding of organ rejection and might aid in improving transplant outcomes. In this review, we look at the latest developments in the study of innate allorecognition and innate immune memory in transplantation.
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Affiliation(s)
- Zeping Gui
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
| | - Mouhamad Al Moussawy
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
| | - Steven M. Sanders
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
| | - Khodor I. Abou-Daya
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
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Hu Z, Zhang Q, He Z, Jia X, Zhang W, Cao X. MHC1/LILRB1 axis as an innate immune checkpoint for cancer therapy. Front Immunol 2024; 15:1421092. [PMID: 38911856 PMCID: PMC11190085 DOI: 10.3389/fimmu.2024.1421092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 05/27/2024] [Indexed: 06/25/2024] Open
Abstract
Immune checkpoint blockades (ICBs) have revolutionized cancer therapy through unleashing anti-tumor adaptive immunity. Despite that, they are usually effective only in a small subset of patients and relapse can occur in patients who initially respond to the treatment. Recent breakthroughs in this field have identified innate immune checkpoints harnessed by cancer cells to escape immunosurveillance from innate immunity. MHC1 appears to be such a molecule expressed on cancer cells which can transmit a negative signal to innate immune cells through interaction with leukocyte immunoglobulin like receptor B1 (LILRB1). The review aims to summarize the current understanding of MHC1/LILRB1 axis on mediating cancer immune evasion with an emphasis on the therapeutic potential to block this axis for cancer therapy. Nevertheless, one should note that this field is still in its infancy and more studies are warranted to further verify the effectiveness and safety in clinical as well as the potential to combine with existing immune checkpoints.
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Affiliation(s)
- Ziyi Hu
- Shanghai Frontiers Science Center for Drug Target Identification and Delivery, and the Engineering Research Center of Cell and Therapeutic Antibody of the Ministry of Education, School of Pharmaceutical Sciences, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, China
| | - Qiaodong Zhang
- Shanghai Frontiers Science Center for Drug Target Identification and Delivery, and the Engineering Research Center of Cell and Therapeutic Antibody of the Ministry of Education, School of Pharmaceutical Sciences, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, China
| | - Zehua He
- Shanghai Frontiers Science Center for Drug Target Identification and Delivery, and the Engineering Research Center of Cell and Therapeutic Antibody of the Ministry of Education, School of Pharmaceutical Sciences, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaojian Jia
- Department of Addiction Medicine, Shenzhen Clinical Research Center for Mental Disorders, Shenzhen Kangning Hospital & Shenzhen Mental Health Center, Shenzhen, China
| | - Wencan Zhang
- Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
| | - Xu Cao
- Shanghai Frontiers Science Center for Drug Target Identification and Delivery, and the Engineering Research Center of Cell and Therapeutic Antibody of the Ministry of Education, School of Pharmaceutical Sciences, National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, China
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Zheng C, Su H, Liu M, Qian Y, Fan H. miRNA‑mRNA network contributes to HBV‑related hepatocellular carcinoma via immune infiltration induced by GRB2. Biomed Rep 2024; 20:90. [PMID: 38682088 PMCID: PMC11046184 DOI: 10.3892/br.2024.1777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 01/05/2024] [Indexed: 05/01/2024] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a critical causative factor in the tumorigenesis and progression of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) serve a critical role in the process of viral infection. However, there has been insufficient evaluation of HBV-associated miRNA-mRNA regulatory networks in HCC. The differential expression levels of miRNAs were compared in HBV-associated HCC tumor and normal tissues using the Gene Expression Omnibus database. The present study evaluated potential target genes of differentially expressed miRNAs using protein-protein interaction network, hub gene, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment and immune infiltration analysis. A total of five miRNAs and seven target genes were identified in the HBV-associated miRNA-mRNA network. miRNA-93 could positively regulate the growth factor receptor bound protein 2 (GRB2) gene, while there was a positive correlation between GRB2 and cancer immune infiltrate function in Tumor Immune Estimation Resource. Collectively, the present study investigated the miRNA-mRNA regulatory network in HCC with HBV infection and showed that miRNA-93 positively regulated immune infiltration-related GRB2. Restoring GRB2 may be a candidate strategy for the treatment of HBV-related HCC.
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Affiliation(s)
- Chuqian Zheng
- Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Hongmeng Su
- Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Min Liu
- School of Life Science and Technology, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Yanyan Qian
- Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Hong Fan
- Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, Jiangsu 210009, P.R. China
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Wang X, Wang J, Peng H, Zuo L, Wang H. Role of immune cell interactions in alcohol-associated liver diseases. LIVER RESEARCH 2024; 8:72-82. [DOI: 10.1016/j.livres.2024.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ma B, Tao M, Li Z, Zheng Q, Wu H, Chen P. Mucosal vaccines for viral diseases: Status and prospects. Virology 2024; 593:110026. [PMID: 38373360 DOI: 10.1016/j.virol.2024.110026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 02/08/2024] [Accepted: 02/12/2024] [Indexed: 02/21/2024]
Abstract
Virus-associated infectious diseases are highly detrimental to human health and animal husbandry. Among all countermeasures against infectious diseases, prophylactic vaccines, which developed through traditional or novel approaches, offer potential benefits. More recently, mucosal vaccines attract attention for their extraordinary characteristics compared to conventional parenteral vaccines, particularly for mucosal-related pathogens. Representatively, coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), further accelerated the research and development efforts for mucosal vaccines by thoroughly investigating existing strategies or involving novel techniques. While several vaccine candidates achieved positive progresses, thus far, part of the current COVID-19 mucosal vaccines have shown poor performance, which underline the need for next-generation mucosal vaccines and corresponding platforms. In this review, we summarized the typical mucosal vaccines approved for humans or animals and sought to elucidate the underlying mechanisms of these successful cases. In addition, mucosal vaccines against COVID-19 that are in human clinical trials were reviewed in detail since this public health event mobilized all advanced technologies for possible solutions. Finally, the gaps in developing mucosal vaccines, potential solutions and prospects were discussed. Overall, rational application of mucosal vaccines would facilitate the establishing of mucosal immunity and block the transmission of viral diseases.
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Affiliation(s)
- Bingjie Ma
- College of Animal Science and Technology, Xinyang Agriculture and Forestry University, Xinyang, China
| | - Mengxiao Tao
- College of Animal Science and Technology, Xinyang Agriculture and Forestry University, Xinyang, China
| | - Zhili Li
- College of Animal Science and Technology, Xinyang Agriculture and Forestry University, Xinyang, China
| | - Quanfang Zheng
- College of Animal Science and Technology, Xinyang Agriculture and Forestry University, Xinyang, China
| | - Haigang Wu
- College of Animal Science and Technology, Xinyang Agriculture and Forestry University, Xinyang, China
| | - Peirong Chen
- College of Animal Science and Technology, Xinyang Agriculture and Forestry University, Xinyang, China.
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Aiello S, Benigni A, Remuzzi G. Tissue-Resident Macrophages in Solid Organ Transplantation: Harmful or Protective? JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1051-1061. [PMID: 38498808 DOI: 10.4049/jimmunol.2300625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 12/27/2023] [Indexed: 03/20/2024]
Abstract
Transplanted organs carry donor immune cells into the recipient, the majority of which are tissue-resident macrophages (TRMs). The role they play in guiding the fate of the transplanted organ toward acceptance or rejection remains elusive. TRMs originate from both embryonic and bone marrow-derived precursors. Embryo-derived TRMs retain the embryonic capability to proliferate, so they are able to self-renew and, theoretically, persist for extended periods of time after transplantation. Bone marrow-derived TRMs do not proliferate and must constantly be replenished by adult circulating monocytes. Recent studies have aimed to clarify the different roles and interactions between donor TRMs, recipient monocytes, and monocyte-derived macrophages (MFs) after organ transplantation. This review aims to shed light on how MFs affect the fate of a transplanted organ by differentiating between the role of donor TRMs and that of MFs derived from graft infiltrating monocytes.
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Affiliation(s)
- Sistiana Aiello
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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Li Z, Zhao M, Yang Y, Zou Z, Zhang L, Jiang F, Du D, Zhou P. Treatment of a MyD88 inhibitor alleviates rejection and inflammation in xenotransplantation by inhibiting dendritic cells activation and trained immunity in macrophages. Int Immunopharmacol 2024; 130:111664. [PMID: 38377850 DOI: 10.1016/j.intimp.2024.111664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 02/22/2024]
Abstract
BACKGROUND Acute vascular rejection (AVR) and systemic inflammation in xenograft recipients (SIXR) negatively impact the xenografts survival, and novel immunosuppressants are required to improve survival outcomes. We previously reported that TJ-M2010-5, a myeloid differentiation factor 88 (MyD88) inhibitor, exerts excellent anti-rejection effects in allogeneic transplantation. The aim of the present study was to evaluate the efficacy of TJ-M2010-5 in preventing AVR and SIXR and to investigate whether combined treatment of TJ-M2010-5 with anti-CD154 antibody (MR1) could prolong xenograft survival furthermore. METHODS A model involving heart transplantation from Sprague-Dawley rats to BALB/c mice was established in vivo, and the xenografts developed typical AVR. Bone marrow-derived dendritic cells and macrophages were cultured to study the underlying mechanisms induced by rat cardiomyocyte lysate stimulation in vitro. RESULTS TJ-M2010-5 monotherapy prolonged xenograft survival, although combination treatment with MR1 further enhanced the anti-AVR and anti-SIXR effects with about 21 days graft survival, compared to monotherapy. TJ-M2010-5 reduced dendritic cell and macrophage activation induced by xenotransplantation, downregulated CD80/CD86 expression, suppressed B-cell activation and anti-donor antibody generation, reduced pro-inflammatory cytokine production and tissue factor expression, and attenuated epigenetic modifications underlying interleukin-6 and tumor necrosis factor-α production in macrophages by inhibiting nuclear factor kappa B nuclear translocation. CONCLUSIONS TJ-M2010-5 attenuated AVR and SIXR and contributed to xenograft survival by inhibiting dendritic cell and macrophage activation. A dual-system inhibition strategy combining TJ-M2010-5 with anti-CD154 antibody achieved better results in xenotransplantation.
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Affiliation(s)
- Zeyang Li
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Minghui Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yang Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhimiao Zou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Limin Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Fengchao Jiang
- Academy of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Dunfeng Du
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, China.
| | - Ping Zhou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, China.
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Sun L, Ma Z, Zhao X, Tan X, Tu Y, Wang J, Chen L, Chen Z, Chen G, Lan P. LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 phosphorylation, enhancing anti-PD1 immunotherapy. J Immunother Cancer 2024; 12:e008367. [PMID: 38272565 PMCID: PMC10824019 DOI: 10.1136/jitc-2023-008367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/29/2023] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND Tumor-infiltrating T cells enter an exhausted or dysfunctional state, which limits antitumor immunity. Among exhausted T cells, a subset of cells with features of progenitor or stem-like cells has been identified as TCF1+ CD8+ T cells that respond to immunotherapy. In contrast to the finding that TCF1 controls epigenetic and transcriptional reprogramming in tumor-infiltrating stem-like T cells, little is known about the regulation of TCF1. Emerging data show that elevated body mass index is associated with outcomes of immunotherapy. However, the mechanism has not been clarified. METHODS We investigated the proliferation of splenic lymphocytes or CD8+ T cells induced by CD3/CD28 stimulation in vitro. We evaluated the effects of low-density lipoprotein (LDL) and LRP11 inhibitors, as well as MAPK13 inhibitors. Additionally, we used shRNA technology to validate the roles of LRP11 and MAPK13. In an in vivo setting, we employed male C57BL/6J injected with B16 cells or MC38 cells to build a tumor model to assess the effects of LDL and LRP11 inhibitors, LRP11 activators, MAPK13 inhibitors on tumor growth. Flow cytometry was used to measure cell proportions and activation status. Molecular interactions and TCF1 status were examined using Western blotting. Moreover, we employed RNA sequencing to investigate the effects of LDL stimulation and MAPK13 inhibition in CD8+ T cells. RESULTS By using a tumor-bearing mouse model, we found that LDL-induced tumor-infiltrating TCF1+PD1+CD8+ T cells. Using a cell-based chimeric receptor screening system, we showed that LRP11 interacted with LDL and activated TCF1. LRP11 activation enhanced TCF1+PD1+CD8+ T-cell-mediated antitumor immunity, consistent with LRP11 blocking impaired T-cell function. Mechanistically, LRP11 activation induces MAPK13 activation. Then, MAPK13 phosphorylates TCF1, leading to increase of stem-like T cells. CONCLUSIONS LRP11-MAPK13-TCF1 enhanced antitumor immunity and induced tumor-infiltrating stem-like T cells.
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Affiliation(s)
- Lingjuan Sun
- Institute of Organ Transplantation,Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, China
| | - Zhibo Ma
- Institute of Organ Transplantation,Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangli Zhao
- Institute of Organ Transplantation,Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaosheng Tan
- Institute of Organ Transplantation,Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhao Tu
- Institute of Organ Transplantation,Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, China
| | - Jingzeng Wang
- Institute of Organ Transplantation,Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, China
| | - Li Chen
- Institute of Organ Transplantation,Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, China
| | - Zhishui Chen
- Institute of Organ Transplantation,Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, China
| | - Gang Chen
- Institute of Organ Transplantation,Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, China
| | - Peixiang Lan
- Institute of Organ Transplantation,Tongji Hospital, Tongji Medical College; Key Laboratory of Organ Transplantation; Ministry of Education, NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Huazhong University of Science and Technology, Wuhan, China
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Kloc M, Halasa M, Kubiak JZ, Ghobrial RM. Invertebrate Immunity, Natural Transplantation Immunity, Somatic and Germ Cell Parasitism, and Transposon Defense. Int J Mol Sci 2024; 25:1072. [PMID: 38256145 PMCID: PMC10815962 DOI: 10.3390/ijms25021072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
While the vertebrate immune system consists of innate and adaptive branches, invertebrates only have innate immunity. This feature makes them an ideal model system for studying the cellular and molecular mechanisms of innate immunity sensu stricto without reciprocal interferences from adaptive immunity. Although invertebrate immunity is evolutionarily older and a precursor of vertebrate immunity, it is far from simple. Despite lacking lymphocytes and functional immunoglobulin, the invertebrate immune system has many sophisticated mechanisms and features, such as long-term immune memory, which, for decades, have been exclusively attributed to adaptive immunity. In this review, we describe the cellular and molecular aspects of invertebrate immunity, including the epigenetic foundation of innate memory, the transgenerational inheritance of immunity, genetic immunity against invading transposons, the mechanisms of self-recognition, natural transplantation, and germ/somatic cell parasitism.
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Affiliation(s)
- Malgorzata Kloc
- Houston Methodist Research Institute, Transplant Immunology, Houston, TX 77030, USA; (M.H.); (R.M.G.)
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Genetics, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
| | - Marta Halasa
- Houston Methodist Research Institute, Transplant Immunology, Houston, TX 77030, USA; (M.H.); (R.M.G.)
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Jacek Z. Kubiak
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine-National Research Institute (WIM-PIB), Szaserow 128, 04-141 Warsaw, Poland;
- Dynamics and Mechanics of Epithelia Group, Faculty of Medicine, Institute of Genetics and Development of Rennes, University of Rennes, CNRS, UMR 6290, 35043 Rennes, France
| | - Rafik M. Ghobrial
- Houston Methodist Research Institute, Transplant Immunology, Houston, TX 77030, USA; (M.H.); (R.M.G.)
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
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Yu Y, Li T, Ou M, Luo R, Chen H, Ren H, Li Z, Sun J, Zhang H, Peng S, Zhao Y, Mei L. OX40L-expressing M1-like macrophage exosomes for cancer immunotherapy. J Control Release 2024; 365:469-479. [PMID: 38040340 DOI: 10.1016/j.jconrel.2023.11.051] [Citation(s) in RCA: 39] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/21/2023] [Accepted: 11/26/2023] [Indexed: 12/03/2023]
Abstract
With only limited clinical patient benefit, focusing on new immune checkpoint pathways could be an important complement to current immune checkpoint drugs. In addition, not only does T cell-mediated adaptive immunity play an important role, but also macrophage-mediated innate immunity, due to its abundant presence in solid tumors. Here, we developed an engineered M1-like macrophage exosome, OX40L M1-exos. OX40L M1-exos can activate the adaptive immunity by activating the OX40/OX40L pathway and can reprogram M2-like tumor-associated macrophages into M1-like macrophages, thereby restoring and enhancing macrophage-mediated innate immunity. Our OX40L M1-exos achieved an effective synergistic effect of innate and adaptive immunity and achieved a potent therapeutic effect in a mouse breast cancer model, effectively inhibiting tumor growth and metastasis. These results suggest that OX40L M1-exos are an attractive therapeutic strategy and may be an important complement to current cancer immunotherapies.
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Affiliation(s)
- Yongkang Yu
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, PR China; Tianjin Institutes of Health Science, Tianjin 301600, PR China; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, PR China
| | - Tingxuan Li
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, PR China; Tianjin Institutes of Health Science, Tianjin 301600, PR China
| | - Meitong Ou
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, PR China; Tianjin Institutes of Health Science, Tianjin 301600, PR China
| | - Ran Luo
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, PR China; Tianjin Institutes of Health Science, Tianjin 301600, PR China
| | - Hongzhong Chen
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, PR China
| | - He Ren
- Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao 266000, PR China
| | - Zimu Li
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, PR China; School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Jie Sun
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, PR China
| | - Hanjie Zhang
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, PR China; Tianjin Institutes of Health Science, Tianjin 301600, PR China
| | - Shaojun Peng
- Zhuhai Institute of Translational Medicine, Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai 519000, PR China
| | - Yanli Zhao
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 21 Nanyang Link, Singapore, 637371, Singapore
| | - Lin Mei
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, PR China; Tianjin Institutes of Health Science, Tianjin 301600, PR China; Shandong Provincial Key Laboratory of Clinical Research for Pancreatic Diseases, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao 266000, PR China.
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Fang XH, Li ZJ, Liu CY, Mor G, Liao AH. Macrophage memory: Types, mechanisms, and its role in health and disease. Immunology 2024; 171:18-30. [PMID: 37702350 DOI: 10.1111/imm.13697] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 09/05/2023] [Indexed: 09/14/2023] Open
Abstract
On the basis of the mechanisms of action and characteristics of immune effects, immunity is commonly categorized into innate and adaptive immunity. Adaptive immunity is associated with the response to non-self-entities and is characterized by high specificity and memory properties. In contrast, innate immunity has traditionally been considered devoid of memory characteristics. However, an increasing number of studies have sought to challenge this conventional immunological dogma and shown that innate immune cells exhibit a more robust and rapid response to secondary stimulation, thus providing evidence of the immunological memory in innate immunity. Macrophages, which are among the most important innate immune cells, can also acquire memory phenotype that facilitates the mediation of recall responses. Macrophage memory is a relatively new concept that is revolutionizing our understanding of macrophage biology and immunological memory and could lead to a new class of vaccines and immunotherapies. In this review, we describe the characteristics and mechanisms of macrophage memory, as well as its essential roles in various diseases.
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Affiliation(s)
- Xu-Hui Fang
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Zhi-Jing Li
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Chun-Yan Liu
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Gil Mor
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
- C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Ai-Hua Liao
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
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40
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Ahuja HK, Azim S, Maluf D, Mas VR. Immune landscape of the kidney allograft in response to rejection. Clin Sci (Lond) 2023; 137:1823-1838. [PMID: 38126208 DOI: 10.1042/cs20230493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 12/23/2023]
Abstract
Preventing kidney graft dysfunction and rejection is a critical step in addressing the nationwide organ shortage and improving patient outcomes. While kidney transplants (KT) are performed more frequently, the overall number of patients on the waitlist consistently exceeds organ availability. Despite improved short-term outcomes in KT, comparable progress in long-term allograft survival has not been achieved. Major cause of graft loss at 5 years post-KT is chronic allograft dysfunction (CAD) characterized by interstitial fibrosis and tubular atrophy (IFTA). Accordingly, proactive prevention of CAD requires a comprehensive understanding of the immune mechanisms associated with either further dysfunction or impaired repair. Allograft rejection is primed by innate immune cells and carried out by adaptive immune cells. The rejection process is primarily facilitated by antibody-mediated rejection (ABMR) and T cell-mediated rejection (TCMR). It is essential to better elucidate the actions of individual immune cell subclasses (e.g. B memory, Tregs, Macrophage type 1 and 2) throughout the rejection process, rather than limiting our understanding to broad classes of immune cells. Embracing multi-omic approaches may be the solution in acknowledging these intricacies and decoding these enigmatic pathways. A transition alongside advancing technology will better allow organ biology to find its place in this era of precision and personalized medicine.
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Affiliation(s)
- Harsimar Kaur Ahuja
- Surgical Sciences Division, Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, U.S.A
| | - Shafquat Azim
- Surgical Sciences Division, Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, U.S.A
| | - Daniel Maluf
- Program of Transplantation, School of Medicine, 29S Greene St, University of Maryland, Baltimore, MD 21201, U.S.A
| | - Valeria R Mas
- Surgical Sciences Division, Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, U.S.A
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41
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Elalouf A, Elalouf H, Rosenfeld A. Modulatory immune responses in fungal infection associated with organ transplant - advancements, management, and challenges. Front Immunol 2023; 14:1292625. [PMID: 38143753 PMCID: PMC10748506 DOI: 10.3389/fimmu.2023.1292625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 11/20/2023] [Indexed: 12/26/2023] Open
Abstract
Organ transplantation stands as a pivotal achievement in modern medicine, offering hope to individuals with end-stage organ diseases. Advancements in immunology led to improved organ transplant survival through the development of immunosuppressants, but this heightened susceptibility to fungal infections with nonspecific symptoms in recipients. This review aims to establish an intricate balance between immune responses and fungal infections in organ transplant recipients. It explores the fundamental immune mechanisms, recent advances in immune response dynamics, and strategies for immune modulation, encompassing responses to fungal infections, immunomodulatory approaches, diagnostics, treatment challenges, and management. Early diagnosis of fungal infections in transplant patients is emphasized with the understanding that innate immune responses could potentially reduce immunosuppression and promise efficient and safe immuno-modulating treatments. Advances in fungal research and genetic influences on immune-fungal interactions are underscored, as well as the potential of single-cell technologies integrated with machine learning for biomarker discovery. This review provides a snapshot of the complex interplay between immune responses and fungal infections in organ transplantation and underscores key research directions.
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Affiliation(s)
- Amir Elalouf
- Department of Management, Bar-Ilan University, Ramat Gan, Israel
| | - Hadas Elalouf
- Information Science Department, Bar-Ilan University, Ramat Gan, Israel
| | - Ariel Rosenfeld
- Information Science Department, Bar-Ilan University, Ramat Gan, Israel
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Li Q, Lin L, Shou P, Liu K, Xue Y, Hu M, Ling W, Huang Y, Du L, Zheng C, Wang X, Zheng F, Zhang T, Wang Y, Shao C, Melino G, Shi Y, Wang Y. MHC class Ib-restricted CD8 + T cells possess strong tumoricidal activities. Proc Natl Acad Sci U S A 2023; 120:e2304689120. [PMID: 37856544 PMCID: PMC10614629 DOI: 10.1073/pnas.2304689120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 08/28/2023] [Indexed: 10/21/2023] Open
Abstract
The importance of classical CD8+ T cells in tumor eradication is well acknowledged. However, the anti-tumor activity of MHC (major histocompatibility complex) Ib-restricted CD8+ T (Ib-CD8+ T) cells remains obscure. Here, we show that CX3CR1-expressing Ib-CD8+ T cells (Ib-restricted CD8+ T cells) highly express cytotoxic factors, austerely resist exhaustion, and effectively eliminate various tumors. These Ib-CD8+ T cells can be primed by MHC Ia (MHC class Ia molecules) expressed on various cell types for optimal activation in a Tbet-dependent manner. Importantly, MHC Ia does not allogeneically activate Ib-CD8+ T cells, rather, sensitizes these cells for T cell receptor activation. Such effects were observed when MHC Ia+ cells were administered to tumor-bearing Kb-/-Db-/-mice. A similar population of tumoricidal CX3CR1+CD8+ T cells was identified in wild-type mice and melanoma patients. Adoptive transfer of Ib-CD8+ T cells to wild-type mice inhibited tumor progression without damaging normal tissues. Taken together, we demonstrate that MHC class Ia can prime Ib-CD8+ T cells for robust tumoricidal activities.
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Affiliation(s)
- Qing Li
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Liangyu Lin
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Peishun Shou
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Keli Liu
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Yueqing Xue
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Mingyuan Hu
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Weifang Ling
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Yin Huang
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Liming Du
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Chunxing Zheng
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Xuefeng Wang
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Fanjun Zheng
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Tao Zhang
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Yu Wang
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
| | - Changshun Shao
- The Third Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu215123, China
| | - Gerry Melino
- Department of Experimental Medicine, Tor Vergata Oncoscience Research, University of Rome Tor Vergata, Rome00133, Italy
| | - Yufang Shi
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
- The Third Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu215123, China
| | - Ying Wang
- Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai200031, China
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Schroth SL, Jones RTL, Thorp EB. Alloantigen Infusion Activates the Transcriptome of Type 2 Conventional Dendritic Cells. Immunohorizons 2023; 7:683-693. [PMID: 37855737 PMCID: PMC10615655 DOI: 10.4049/immunohorizons.2300067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 09/13/2023] [Indexed: 10/20/2023] Open
Abstract
Recent studies have revealed novel molecular mechanisms by which innate monocytic cells acutely recognize and respond to alloantigen with significance to allograft rejection and tolerance. What remains unclear is the single-cell heterogeneity of the innate alloresponse, particularly the contribution of dendritic cell (DC) subsets. To investigate the response of these cells to exposure of alloantigen, C57BL/6J mice were administered live allogenic BALB/cJ splenic murine cells versus isogenic cells. In parallel, we infused apoptotic allogenic and isogenic cells, which have been reported to modulate immunity. Forty-eight hours after injection, recipient spleens were harvested, enriched for DCs, and subjected to single-cell mRNA sequencing. Injection of live cells induced a greater transcriptional change across DC subsets compared with apoptotic cells. In the setting of live cell infusion, type 2 conventional DCs (cDC2s) were most transcriptionally responsive with a Ccr2+ cDC2 subcluster uniquely responding to the presence of alloantigen compared with the isogenic control. In vitro experimentation confirmed unique activation of CCR2+ cDC2s following alloantigen exposure. Candidate receptors of allorecognition in other innate populations were interrogated and A type paired Ig-like receptors were found to be increased in the cDC2 population following alloexposure. These results illuminate previously unclear distinctions between therapeutic infusions of live versus apoptotic allogenic cells and suggest a role for cDC2s in innate allorecognition. More critically, these studies allow for future interrogation of the transcriptional response of immune cells in the setting of alloantigen exposure in vivo, encouraging assessment of novel pathways and previously unexamined receptors in this setting.
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Affiliation(s)
- Samantha L. Schroth
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Rebecca T. L. Jones
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Edward B. Thorp
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
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Wu Z, Liang J, Zhu S, Liu N, Zhao M, Xiao F, Li G, Yu C, Jin C, Ma J, Sun T, Zhu P. Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection. Front Immunol 2023; 14:1251028. [PMID: 37781362 PMCID: PMC10535112 DOI: 10.3389/fimmu.2023.1251028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 08/29/2023] [Indexed: 10/03/2023] Open
Abstract
Aims Understanding the cellular mechanisms underlying early allograft rejection is crucial for the development of effective immunosuppressant strategies. This study aims to investigate the cellular composition of graft-infiltrating cells during the early rejection stage at a single-cell level and identify potential therapeutic targets. Methods A heterotopic heart transplant model was established using enhanced green fluorescent protein (eGFP)-expressing mice as recipients of allogeneic or syngeneic grafts. At 3 days post-transplant, eGFP-positive cells infiltrating the grafts were sorted and subjected to single-cell RNA-seq analysis. Potential molecular targets were evaluated by assessing graft survival and functions following administration of various pharmacological inhibitors. Results A total of 27,053 cells recovered from syngrafts and allografts were classified into 20 clusters based on expression profiles and annotated with a reference dataset. Innate immune cells, including monocytes, macrophages, neutrophils, and dendritic cells, constituted the major infiltrating cell types (>90%) in the grafts. Lymphocytes, fibroblasts, and endothelial cells represented a smaller population. Allografts exhibited significantly increased proportions of monocyte-derived cells involved in antigen processing and presentation, as well as activated lymphocytes, as compared to syngrafts. Differential expression analysis revealed upregulation of interferon activation-related genes in the innate immune cells infiltrating allografts. Pro-inflammatory polarization gene signatures were also enriched in these infiltrating cells of allografts. Gene profiling and intercellular communication analysis identified natural killer cells as the primary source of interferon-γ signaling, activating inflammatory monocytes that displayed strong signals of major histocompatibility complexes and co-stimulatory molecules. The inflammatory response was also associated with promoted T cell proliferation and activation in allografts during the early transplant stages. Notably, caspase-1 exhibited specific upregulation in inflammatory monocytes in response to interferon signaling. The regulon analysis also revealed a significant enrichment of interferon-related motifs within the transcriptional regulatory network of downstream inflammatory genes including caspase-1. Remarkably, pharmacological inhibition of caspase-1 was shown to reduce immune infiltration, prevent acute graft rejection, and improve cardiac contractile function. Conclusion The single-cell transcriptional profile highlighted the crucial role of caspase-1 in interferon-mediated inflammatory monocytes infiltrating heart transplants, suggesting its potential as a therapeutic target for attenuating rejection.
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Affiliation(s)
- Zhichao Wu
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, China
- Department of Thoracic Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Jialiang Liang
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, China
| | - Shuoji Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, China
| | - Nanbo Liu
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, China
| | - Mingyi Zhao
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, China
| | - Fei Xiao
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, China
| | - Guanhua Li
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, China
| | - Changjiang Yu
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, China
| | - Chengyu Jin
- Department of Thoracic Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Jinshan Ma
- Department of Thoracic Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Tucheng Sun
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, China
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou Key Laboratory of Cardiac Pathogenesis and Prevention, Guangzhou, Guangdong, China
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Lin X, Li Z, Gong G, Wang H, Fang X, Mor G, Liao A. The immune checkpoint protein PD-1: Its emerging regulatory role in memory T cells. J Reprod Immunol 2023; 159:104130. [PMID: 37591180 DOI: 10.1016/j.jri.2023.104130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/30/2023] [Accepted: 08/06/2023] [Indexed: 08/19/2023]
Abstract
Immunological memory helps the body rapidly develop immune defense when it re-encounters a bacterial or viral strain or encounters a similar mutation in healthy cells. The immune checkpoint molecule programmed cell death 1 (PD-1) influences memory T cell differentiation. However, the mechanism by which PD-1 regulates the development and maintenance of memory T cells and its impact on memory T cells function remain unclear. In this review, we first discuss the structure and function of PD-1 and then summarize the roles of PD-1 as a marker of tumor memory T cells and in tumor immunotherapy. We also discuss the potential mechanisms through which PD-1 regulates memory T cells development and maintenance during immune diseases such as viral infection-mediated diseases, psoriasis, and rheumatoid arthritis, and list the effects of PD-1 on memory T cells in pregnancy and their function in maternal-fetal immune balance. A complete understanding of how PD-1 influences the development, maintenance, and function of memory T cells will provide new insights into the prevention and treatment of immune-related diseases.
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Affiliation(s)
- Xinxiu Lin
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Zhijing Li
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Guangshun Gong
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Huan Wang
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Xuhui Fang
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Gil Mor
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; C.S. Mott Center for Human Growth and Development, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Aihua Liao
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
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Lamarthée B, Callemeyn J, Van Herck Y, Antoranz A, Anglicheau D, Boada P, Becker JU, Debyser T, De Smet F, De Vusser K, Eloudzeri M, Franken A, Gwinner W, Koshy P, Kuypers D, Lambrechts D, Marquet P, Mathias V, Rabant M, Sarwal MM, Senev A, Sigdel TK, Sprangers B, Thaunat O, Tinel C, Van Brussel T, Van Craenenbroeck A, Van Loon E, Vaulet T, Bosisio F, Naesens M. Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection. Nat Commun 2023; 14:4359. [PMID: 37468466 DOI: 10.1038/s41467-023-39859-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 06/28/2023] [Indexed: 07/21/2023] Open
Abstract
Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the cell-to-cell interactions of the alloreactive inflammatory infiltrate. Here, we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies with varying phenotypes and severities of rejection and without rejection, and identified cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived FCGR3A+ monocytes, FCGR3A+ NK cells and the severity of intragraft inflammation. Activated FCGR3A+ monocytes overexpressed CD47 and LILR genes and increased paracrine signaling pathways promoting T cell infiltration. FCGR3A+ NK cells overexpressed FCRL3, suggesting that antibody-dependent cytotoxicity is a central mechanism of NK-cell mediated graft injury. Multiplexed immunofluorescence using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results highlight the central involvement of innate immune cells in the pathogenesis of allograft rejection and identify several potential therapeutic targets that might improve allograft longevity.
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Affiliation(s)
- Baptiste Lamarthée
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Université de Franche-Comté, UBFC, EFS, Inserm UMR RIGHT, Besançon, France
| | - Jasper Callemeyn
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Yannick Van Herck
- Department of Oncology, Laboratory for Experimental Oncology, KU Leuven, Leuven, Belgium
| | - Asier Antoranz
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium
| | - Dany Anglicheau
- Department of Nephrology and Kidney Transplantation, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
- Université Paris Cité, Inserm U1151, Necker Enfants-Malades Institute, Paris, France
| | - Patrick Boada
- Division of Multi-Organ Transplantation, Department of Surgery, UCSF, 513 Parnassus, San Francisco, CA, USA
| | - Jan Ulrich Becker
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Tim Debyser
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Frederik De Smet
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium
| | - Katrien De Vusser
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Maëva Eloudzeri
- Université Paris Cité, Inserm U1151, Necker Enfants-Malades Institute, Paris, France
| | - Amelie Franken
- VIB Center for Cancer Biology, Leuven, Belgium
- Department of Human Genetics, Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium
| | - Wilfried Gwinner
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Priyanka Koshy
- Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Dirk Kuypers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Diether Lambrechts
- VIB Center for Cancer Biology, Leuven, Belgium
- Department of Human Genetics, Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium
| | - Pierre Marquet
- Department of Pharmacology and Transplantation, University of Limoges, Inserm U1248, Limoges University Hospital, Limoges, France
| | - Virginie Mathias
- EFS, HLA Laboratory, Décines, France
- Université Claude Bernard Lyon I, Inserm U1111, CNRS UMR5308, CIRI, Ecole Normale Supérieure de Lyon, Lyon, France
| | - Marion Rabant
- Université Paris Cité, Inserm U1151, Necker Enfants-Malades Institute, Paris, France
- Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Minnie M Sarwal
- Division of Multi-Organ Transplantation, Department of Surgery, UCSF, 513 Parnassus, San Francisco, CA, USA
| | - Aleksandar Senev
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Histocompatibility and Immunogenetics Laboratory, Red Cross-Flanders, Mechelen, Belgium
| | - Tara K Sigdel
- Division of Multi-Organ Transplantation, Department of Surgery, UCSF, 513 Parnassus, San Francisco, CA, USA
| | - Ben Sprangers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Olivier Thaunat
- Université Claude Bernard Lyon I, Inserm U1111, CNRS UMR5308, CIRI, Ecole Normale Supérieure de Lyon, Lyon, France
- Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, Lyon, France
| | - Claire Tinel
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Université de Franche-Comté, UBFC, EFS, Inserm UMR RIGHT, Besançon, France
- Department of Nephrology and Kidney Transplantation, Dijon Hospital, Dijon, France
| | - Thomas Van Brussel
- VIB Center for Cancer Biology, Leuven, Belgium
- Department of Human Genetics, Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium
| | - Amaryllis Van Craenenbroeck
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Elisabet Van Loon
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Thibaut Vaulet
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Francesca Bosisio
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium.
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium.
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Li X, Wu J, Zhu S, Wei Q, Wang L, Chen J. Intragraft immune cells: accomplices or antagonists of recipient-derived macrophages in allograft fibrosis? Cell Mol Life Sci 2023; 80:195. [PMID: 37395809 DOI: 10.1007/s00018-023-04846-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 05/22/2023] [Accepted: 06/21/2023] [Indexed: 07/04/2023]
Abstract
Organ fibrosis caused by chronic allograft rejection is a major concern in the field of transplantation. Macrophage-to-myofibroblast transition plays a critical role in chronic allograft fibrosis. Adaptive immune cells (such as B and CD4+ T cells) and innate immune cells (such as neutrophils and innate lymphoid cells) participate in the occurrence of recipient-derived macrophages transformed to myofibroblasts by secreting cytokines, which eventually leads to fibrosis of the transplanted organ. This review provides an update on the latest progress in understanding the plasticity of recipient-derived macrophages in chronic allograft rejection. We discuss here the immune mechanisms of allograft fibrosis and review the reaction of immune cells in allograft. The interactions between immune cells and the process of myofibroblast formulation are being considered for the potential therapeutic targets of chronic allograft fibrosis. Therefore, research on this topic seems to provide novel clues for developing strategies for preventing and treating allograft fibrosis.
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Affiliation(s)
- Xiaoping Li
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
- Department of Pediatrics, First Hospital of Jilin University, Changchun, 130021, Jilin, China
| | - Jing Wu
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Shan Zhu
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Qiuyu Wei
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Liyan Wang
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China
| | - Jingtao Chen
- Cancer Center, First Hospital of Jilin University, Changchun, 130021, Jilin, China.
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, 130061, Jilin, China.
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Gao Y, Yuan Y, Wen S, Chen Y, Zhang Z, Feng Y, Jiang B, Ma S, Hu R, Fang C, Ruan X, Yuan Y, Fang X, Luo C, Meng Z, Wang X, Guo X. Dual role of ANGPTL8 in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis. Oncogenesis 2023; 12:26. [PMID: 37188659 PMCID: PMC10185523 DOI: 10.1038/s41389-023-00473-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 04/19/2023] [Accepted: 04/25/2023] [Indexed: 05/17/2023] Open
Abstract
The interplay between hepatocellular carcinoma (HCC) cells and the tumor microenvironment is essential for hepatocarcinogenesis, but their contributions to HCC development are incompletely understood. We assessed the role of ANGPTL8, a protein secreted by HCC cells, in hepatocarcinogenesis and the mechanisms through which ANGPTL8 mediates crosstalk between HCC cells and tumor-associated macrophages. Immunohistochemical, Western blotting, RNA-Seq, and flow cytometry analyses of ANGPTL8 were performed. A series of in vitro and in vivo experiments were conducted to reveal the role of ANGPTL8 in the progression of HCC. ANGPTL8 expression was positively correlated with tumor malignancy in HCC, and high ANGPTL8 expression was associated with poor overall survival (OS) and disease-free survival (DFS). ANGPTL8 promoted HCC cell proliferation in vitro and in vivo, and ANGPTL8 KO inhibited the development of HCC in both DEN-induced and DEN-plus-CCL4-induced mouse HCC tumors. Mechanistically, the ANGPTL8-LILRB2/PIRB interaction promoted polarization of macrophages to the immunosuppressive M2 phenotype in macrophages and recruited immunosuppressive T cells. In hepatocytes, ANGPTL8-mediated stimulation of LILRB2/PIRB regulated the ROS/ERK pathway and upregulated autophagy, leading to the proliferation of HCC cells. Our data support the notion that ANGPTL8 has a dual role in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis.
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Grants
- 82073232, 82101632, 81700769, 81641028 National Natural Science Foundation of China (National Science Foundation of China)
- The Hubei Science & Technology Department Foundation (2020CFB558, 2018ACA162), the Key Projects of Hubei Education (D20202103), the Department of Biomedical Research Foundation, Hubei University of Medicine (HBMUPI201803), the Department of Education Cultivating Project for Young Scholars at Hubei University of Medicine (2018QDJZR02), the Innovative Research Program for Graduates of Hubei University of Medicine (YC2020039, YC2020002, YC2019003, YC2019008), the Advantages Discipline Group (medicine) Project in Higher Education of Hubei Province (2022XKQT3,2022XKQY1) and the Scientific Research Project of Shiyan Science and Technology Bureau, 21Y06, 21Y38).Hubei Province’s Outstanding Medical Academic Leader Program.
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Affiliation(s)
- Yujiu Gao
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
- Department of Nephrology, Taihe Hospital, 442000, Shiyan, China
- Hubei Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, 442000, Shiyan, China
| | - Yue Yuan
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
- College of Pharmacy, Hubei University of Medicine, 442000, Shiyan, China
- Department of Anesthesiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
| | - Shu Wen
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
| | - Yanghui Chen
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
| | - Zongli Zhang
- Institute of Pediatric Disease, Taihe Hospital, 442000, Shiyan, China
| | - Ying Feng
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
| | - Bin Jiang
- Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital, 442000, Shiyan, China
| | - Shinan Ma
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
| | - Rong Hu
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
| | - Chen Fang
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
| | - Xuzhi Ruan
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
| | - Yahong Yuan
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
| | - Xinggang Fang
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
| | - Chao Luo
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China
| | - Zhongji Meng
- Department of Infectious Diseases, Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, 442000, Shiyan, China.
| | - Xiaoli Wang
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China.
- Hubei Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, 442000, Shiyan, China.
| | - Xingrong Guo
- Department of Critical Care Medicine, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, China.
- Hubei Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, 442000, Shiyan, China.
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Jelinek AL, Futas J, Burger PA, Horin P. Comparative genomics of the Leukocyte Receptor Complex in carnivores. Front Immunol 2023; 14:1197687. [PMID: 37234165 PMCID: PMC10206138 DOI: 10.3389/fimmu.2023.1197687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 04/27/2023] [Indexed: 05/27/2023] Open
Abstract
Background The mammalian Leukocyte Receptor Complex (LRC) chromosomal region may contain gene families for the killer cell immunoglobulin-like receptor (KIR) and/or leukocyte immunoglobulin-like receptor (LILR) collections as well as various framing genes. This complex region is well described in humans, mice, and some domestic animals. Although single KIR genes are known in some Carnivora, their complements of LILR genes remain largely unknown due to obstacles in the assembly of regions of high homology in short-read based genomes. Methods As part of the analysis of felid immunogenomes, this study focuses on the search for LRC genes in reference genomes and the annotation of LILR genes in Felidae. Chromosome-level genomes based on single-molecule long-read sequencing were preferentially sought and compared to representatives of the Carnivora. Results Seven putatively functional LILR genes were found across the Felidae and in the Californian sea lion, four to five genes in Canidae, and four to nine genes in Mustelidae. They form two lineages, as seen in the Bovidae. The ratio of functional genes for activating LILRs to inhibitory LILRs is slightly in favor of inhibitory genes in the Felidae and the Canidae; the reverse is seen in the Californian sea lion. This ratio is even in all of the Mustelidae except the Eurasian otter, which has a predominance of activating LILRs. Various numbers of LILR pseudogenes were identified. Conclusions The structure of the LRC is rather conservative in felids and the other Carnivora studied. The LILR sub-region is conserved within the Felidae and has slight differences in the Canidae, but it has taken various evolutionary paths in the Mustelidae. Overall, the process of pseudogenization of LILR genes seems to be more frequent for activating receptors. Phylogenetic analysis found no direct orthologues across the Carnivora which corroborate the rapid evolution of LILRs seen in mammals.
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Affiliation(s)
- April L. Jelinek
- Department of Animal Genetics, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno (VETUNI), Brno, Czechia
| | - Jan Futas
- Department of Animal Genetics, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno (VETUNI), Brno, Czechia
- Research Group Animal Immunogenomics, Central European Institute of Technology (CEITEC) VETUNI, Brno, Czechia
| | - Pamela A. Burger
- Research Institute of Wildlife Ecology, University of Veterinary Medicine Vienna (VETMEDUNI), Vienna, Austria
| | - Petr Horin
- Department of Animal Genetics, Faculty of Veterinary Medicine, University of Veterinary Sciences Brno (VETUNI), Brno, Czechia
- Research Group Animal Immunogenomics, Central European Institute of Technology (CEITEC) VETUNI, Brno, Czechia
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50
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Lackner K, Ebner S, Watschinger K, Maglione M. Multiple Shades of Gray-Macrophages in Acute Allograft Rejection. Int J Mol Sci 2023; 24:8257. [PMID: 37175964 PMCID: PMC10179242 DOI: 10.3390/ijms24098257] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 04/27/2023] [Accepted: 05/01/2023] [Indexed: 05/15/2023] Open
Abstract
Long-term results following solid organ transplantation do not mirror the excellent short-term results achieved in recent decades. It is therefore clear that current immunosuppressive maintenance protocols primarily addressing the adaptive immune system no longer meet the required clinical need. Identification of novel targets addressing this shortcoming is urgently needed. There is a growing interest in better understanding the role of the innate immune system in this context. In this review, we focus on macrophages, which are known to prominently infiltrate allografts and, during allograft rejection, to be involved in the surge of the adaptive immune response by expression of pro-inflammatory cytokines and direct cytotoxicity. However, this active participation is janus-faced and unspecific targeting of macrophages may not consider the different subtypes involved. Under this premise, we give an overview on macrophages, including their origins, plasticity, and important markers. We then briefly describe their role in acute allograft rejection, which ranges from sustaining injury to promoting tolerance, as well as the impact of maintenance immunosuppressants on macrophages. Finally, we discuss the observed immunosuppressive role of the vitamin-like compound tetrahydrobiopterin and the recent findings that suggest the innate immune system, particularly macrophages, as its target.
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Affiliation(s)
- Katharina Lackner
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (K.L.); (S.E.)
| | - Susanne Ebner
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (K.L.); (S.E.)
| | - Katrin Watschinger
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Manuel Maglione
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria; (K.L.); (S.E.)
- Department of Visceral, Transplant, and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
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