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Louis K, Tabib T, Macedo C, Wang J, Cantalupo P, Chandran U, Gu X, Lucas M, Randhawa P, Abundis M, Das J, Singh H, Lefaucheur C, Metes D. High-dimensional profiling of immune responses to kidney transplant reveals heterogeneous T helper 1 and B cell effectors associated with rejection. Am J Transplant 2025; 25:706-719. [PMID: 39419342 PMCID: PMC11972895 DOI: 10.1016/j.ajt.2024.10.009] [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: 07/12/2024] [Revised: 09/20/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024]
Abstract
Rejection is a primary cause of allograft dysfunction after kidney transplantation. The diversity of immune subpopulations involved in the different endotypes of rejection remains to be delineated at single-cell resolution. In a cohort of 76 kidney transplant recipients, we conducted high-dimensional immune phenotyping of blood CD4 T and B cells, single-cell RNA and T/B cell receptor sequencing, and plasma cytokine profiling. Phenotypic, transcriptional, and clonal states of CD4T and B cells could significantly distinguish stable allograft states from rejection. Patients undergoing T cell-mediated rejection displayed accumulation of clonally expanded cytotoxic T helper (Th)1 cells and Th17-like cells, associated with predominant naive B cell responses. In contrast, antibody-mediated rejection was characterized by clonal expansion of Th1-polarized T follicular helper cells and effector T-bet+ memory B cells, both of which strongly expressed interleukin 12 and tumor necrosis factor-signaling pathways. Plasma cytokine analysis confirmed mixed Th1/Th17 and Th1/T follicular helper cell-driven inflammatory profiles distinguishing T cell-mediated rejection and antibody-mediated rejection, respectively. CD4T and B cell subpopulations and signatures were validated using bulk RNA-seq analysis of matched kidney allografts and using an independent single-cell RNA-seq data set. These data improve mechanistic understanding of the immune pathogenesis of rejection and support the development of more specific immunosuppressive therapies to treat allograft rejection.
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Affiliation(s)
- Kevin Louis
- Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Human Immunology and Immunopathology, Inserm UMR 976, Université Paris Cité, Paris, France.
| | - Tracy Tabib
- Center for Systems Immunology and Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Camila Macedo
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Jiefei Wang
- Department of Biomedical Informatics and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Paul Cantalupo
- Department of Biomedical Informatics and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Uma Chandran
- Department of Biomedical Informatics and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Xinyan Gu
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Michelle Lucas
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Parmjeet Randhawa
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Marisa Abundis
- Center for Systems Immunology and Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jishnu Das
- Center for Systems Immunology and Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Harinder Singh
- Center for Systems Immunology and Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Carmen Lefaucheur
- Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Human Immunology and Immunopathology, Inserm UMR 976, Université Paris Cité, Paris, France
| | - Diana Metes
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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Changizi M, Motalleb G, Yaghobi R, Afshari A, Roozbeh J. The impact of gamma interferon on BK virus candidate microRNAs and related miRNAs in kidney transplant patients with BK infection. Sci Rep 2025; 15:8880. [PMID: 40087365 PMCID: PMC11909238 DOI: 10.1038/s41598-025-93503-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 03/07/2025] [Indexed: 03/17/2025] Open
Abstract
Kidney transplant recipients (KTRs) with impaired immune systems may develop BKV nephropathy (BKVN). BKVN and allograft rejection may harm transplanted kidneys. BKV replicates via miR-B1-5p and 3p in order to escape from host's immunological response. BKV alters KTR and viral gene expression and miRNA profiles. In an inflammatory setting, IFN-γ may initiate the removal of pathogens by inducing an immune response. It has antiviral immunity, which may prevent the virus from replicating by preventing the synthesis of BK virus proteins. Antiviral miRNAs like miR-29a are also produced in response to IFN-γ activation. Thus, we investigated these modifications as putative biomarkers for evaluating viral infection and the regulatory web that arises from their expression during infection and the emergence of post-transplant problems. This study was carried out on KTRs. Our research, which aimed to quantify and examine the amounts of cellular miRNA-29a, IFN-γ gene, BKV-miR-B1-5p and 3p from urine and blood in KT patient groups, has the potential to guide future research in the field. Patients with BKVN (BK-), patients without an active BKV infection (BK-), patients with a history of transplant rejection (Reject), patients without an active history of transplant rejection (Non reject), and a control group were among these groups. The Syber green real-time PCR was employed for the measurements and analysis. The findings of our investigation demonstrated that BK virus-caused kidney tissue damage (tissue), patients with an active BK virus infection (BK+), and KTRs who had previously experienced transplant rejection all showed less IFN-γ gene expression in comparison with control. These patients showed upper levels of miR-29a gene expression than the control group. Furthermore, these patients' gene expressions of miR-B1-5p and 3p showed higher in comparison with those of the control group. To date, there is no report on the effect of IFN-γ on the expression of BK polyomavirus miRNAs and related miRNAs in kidney transplant recipients with nephropathy compared to kidney transplant recipients without nephropathy in the Iranian population. Therefore, the results of this study can be used as a strategy to combat viral infections and pathogenesis caused by BK polyomavirus in kidney transplantation.
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Affiliation(s)
- Maryam Changizi
- Division of Cell and Molecular Biology, Department of Biology, Faculty of Science, University of Zabol, Zabol, 98613-35856, Islamic Republic of Iran
| | - Gholamreza Motalleb
- Division of Cell and Molecular Biology, Department of Biology, Faculty of Science, University of Zabol, Zabol, 98613-35856, Islamic Republic of Iran.
| | - Ramin Yaghobi
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, 71937-11351, Iran
| | - Afsoon Afshari
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, 71937-11351, Iran
| | - Jamshid Roozbeh
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, 71937-11351, Iran
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Cucchiari D, Podestà MA, Ponticelli C. Pathophysiology of rejection in kidney transplantation. Expert Rev Clin Immunol 2024; 20:1471-1481. [PMID: 39467249 DOI: 10.1080/1744666x.2024.2421310] [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: 02/04/2024] [Accepted: 10/04/2024] [Indexed: 10/30/2024]
Abstract
INTRODUCTION Rejection remains a major obstacle to successful kidney transplantation. The complex pathophysiology of rejection depends on a fine-tuned interplay between the innate and adaptive immune systems. AREAS COVERED This review provides a comprehensive analysis of the pathophysiology of rejection of kidney grafts, performed through careful selection of most relevant papers available on the topic in the PubMed database. The two types of rejection usually observed at the kidney biopsy, i.e. cellular and humoral rejection, are described with an accurate outline of the biological processes that lead to their development. EXPERT OPINION The incidence of T-cell-mediated rejection is decreasing, and most cases promptly respond to appropriate immunosuppression. However, late diagnosis or incomplete response to treatment may have deleterious consequences in the long term. The main issue is represented by antibody-mediated rejection, which unsatisfactorily responds to aggressive immunosuppression, especially when diagnosed late. Prevention of acute ABMR rests on HLA-specific antibody detection prior to transplantation, adequate immunosuppression, and optimal patients' compliance. Late diagnosis and poor response to treatment inevitably lead to chronic ABMR, for which no therapies are currently available.
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Affiliation(s)
- David Cucchiari
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Barcelona, Spain
| | - Manuel Alfredo Podestà
- Transplantation Research Center, Renal Division, Brigham and Women's Hopsital, Harvard Medical School, Boston, MA, USA
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Negi S, Rutman AK, Saw CL, Paraskevas S, Tchervenkov J. Pretransplant, Th17 dominant alloreactivity in highly sensitized kidney transplant candidates. FRONTIERS IN TRANSPLANTATION 2024; 3:1336563. [PMID: 38993777 PMCID: PMC11235243 DOI: 10.3389/frtra.2024.1336563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 03/21/2024] [Indexed: 07/13/2024]
Abstract
Introduction Sensitization to donor human leukocyte antigen (HLA) molecules prior to transplantation is a significant risk factor for delayed access to transplantation and to long-term outcomes. Memory T cells and their cytokines play a pivotal role in shaping immune responses, thereby increasing the risk of allograft rejection among highly sensitized patients. This study aims to elucidate the precise contribution of different CD4+ memory T cell subsets to alloreactivity in highly sensitized (HS) kidney transplant recipients. Methods and results Stimulation of peripheral blood mononuclear cells (PBMC) with various polyclonal stimulating agents to assess non-specific immune responses revealed that HS patients exhibit elevated immune reactivity even before kidney transplantation, compared to non-sensitized (NS) patients. HS patients' PBMC displayed higher frequencies of CD4+ T cells expressing IFNγ, IL4, IL6, IL17A, and TNFα and secreted relatively higher levels of IL17A and IL21 upon stimulation with PMA/ionomycin. Additionally, PBMC from HS patients stimulated with T cell stimulating agent phytohemagglutinin (PHA) exhibited elevated expression levels of IFNγ, IL4 and, IL21. On the other hand, stimulation with a combination of resiquimod (R848) and IL2 for the activation of memory B cells demonstrated higher expression of IL17A, TNFα and IL21, as determined by quantitative real-time PCR. A mixed leukocyte reaction (MLR) assay, employing third-party donor antigen presenting cells (APCs), was implemented to evaluate the direct alloreactive response. HS patients demonstrated notably higher frequencies of CD4+ T cells expressing IL4, IL6 and IL17A. Interestingly, APCs expressing recall HLA antigens triggered a stronger Th17 response compared to APCs lacking recall HLA antigens in sensitized patients. Furthermore, donor APCs induced higher activation of effector memory T cells in HS patients as compared to NS patients. Conclusion These results provide an assessment of pretransplant alloreactive T cell subsets in highly sensitized patients and emphasize the significance of Th17 cells in alloimmune responses. These findings hold promise for the development of treatment strategies tailored to sensitized kidney transplant recipients, with potential clinical implications.
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Affiliation(s)
- Sarita Negi
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
- Human Islet Transplantation Laboratory, McGill University Health Centre, Montréal, QC, Canada
| | | | - Chee Loong Saw
- HLA Laboratory, Division of Hematology, McGill University Health Centre, Montréal, QC, Canada
| | - Steven Paraskevas
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
- Human Islet Transplantation Laboratory, McGill University Health Centre, Montréal, QC, Canada
- Department of Surgery, McGill University, Montréal, QC, Canada
- Division of General Surgery and Multi-Organ Transplant Program, Department of Surgery, McGill University Health Centre, Montréal, QC, Canada
| | - Jean Tchervenkov
- Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
- Department of Surgery, McGill University, Montréal, QC, Canada
- Division of General Surgery and Multi-Organ Transplant Program, Department of Surgery, McGill University Health Centre, Montréal, QC, Canada
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Ni B, Zhang D, Zhou H, Zheng M, Wang Z, Tao J, Han Z, Ju X, Tan R, Gu M. IL-34 attenuates acute T cell-mediated rejection following renal transplantation by upregulating M2 macrophages polarization. Heliyon 2024; 10:e24028. [PMID: 38230243 PMCID: PMC10789621 DOI: 10.1016/j.heliyon.2024.e24028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/16/2023] [Accepted: 01/02/2024] [Indexed: 01/18/2024] Open
Abstract
Objective To investigate the role of Interleukin-34 (IL-34) in acute T cell-mediated rejection (TCMR) following renal transplantation. Methods The mice acute TCMR model of renal transplantation was established and identified by hematoxylin and eosin (HE) and immunohistochemistry (IHC) staining. Then, IHC staining of IL-34 was also performed to determine the expression of IL-34 in allografts. Recipients were infected with IL-34 overexpression adeno-associated virus, infection efficiency of which was estimated by enzyme linked immunosorbent assay (ELISA), Western blot, and immunofluorescence. HE and IHC staining were used to estimate the grades of TCMR. Flow cytometry was performed on lymphocytes in spleens of recipients including regulatory T cells (Tregs) and M2 macrophages. The expression of cytokines in vivo was analyzed by Mouse Cytokine Grp I Panel. Finally, Tregs and M2 macrophages were cultured in vitro and treated with IL-34 to observe the effects of IL-34 on the differentiation of the cells. Results The mouse TCMR model was successfully established by HE, periodic acid shiff (PAS), CD4 and CD8 IHC staining. The expression of IL-34 was significantly decreased in allografts with TCMR. BALB/c mice were successfully infected with IL-34 overexpression adeno-associated virus. Subsequently, the grade of rejection in mice TCMR model was evaluated by HE and IHC staining according to Banff criteria. It is suggested that the grade of TCMR in IL-34 overexpressed mice was significantly decreased. IHC staining and Flow cytometry showed that the proportion of Tregs and M2 macrophages in the spleens and allografts were significantly increased in IL-34 overexpressed mice. Serum levels of interferon-gamma (IFN-γ), IL-17 and tumor necrosis factor-alpha (TNF-α) were downregulated in IL-34 overexpressed mice. Moreover, IL-34 could promote macrophage M2 polarization, while failed to promote differentiation of naïve T cells into Tregs in vitro. Conclusion Overexpression of IL-34 may attenuate the progression of TCMR episodes in allografts by increasing the polarization of M2 macrophages in the spleens and allografts, which may become a potential therapeutic strategy for TCMR.
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Affiliation(s)
- Bin Ni
- Department of Urology, the Second Affiliated Hospital of Nanjing Medical University, 121# Jiangjiayuan Road, Nanjing, Jiangsu, China
| | - Dongliang Zhang
- Department of Urology, the Second Affiliated Hospital of Nanjing Medical University, 121# Jiangjiayuan Road, Nanjing, Jiangsu, China
| | - Hai Zhou
- Department of Urology, the Second Affiliated Hospital of Nanjing Medical University, 121# Jiangjiayuan Road, Nanjing, Jiangsu, China
| | - Ming Zheng
- Department of Urology, the Second Affiliated Hospital of Nanjing Medical University, 121# Jiangjiayuan Road, Nanjing, Jiangsu, China
| | - Zijie Wang
- Department of Urology, the First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, Jiangsu, China
| | - Jun Tao
- Department of Urology, the First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, Jiangsu, China
| | - Zhijian Han
- Department of Urology, the First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, Jiangsu, China
| | - Xiaobin Ju
- Department of Urology, the First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, Jiangsu, China
| | - Ruoyun Tan
- Department of Urology, the First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, Jiangsu, China
| | - Min Gu
- Department of Urology, the Second Affiliated Hospital of Nanjing Medical University, 121# Jiangjiayuan Road, Nanjing, Jiangsu, China
- Department of Urology, the First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, Jiangsu, China
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Wu C, Xu J, Zhang Z, Wei D, Xu Y, Zhao Y. The Effects of IL-23/IL-18-Polarized Neutrophils on Renal Ischemia-Reperfusion Injury and Allogeneic-Skin-Graft Rejection in Mice. Biomedicines 2023; 11:3148. [PMID: 38137369 PMCID: PMC10740676 DOI: 10.3390/biomedicines11123148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 10/26/2023] [Accepted: 11/20/2023] [Indexed: 12/24/2023] Open
Abstract
Neutrophils display heterogeneity and plasticity with different subgroups and immune-regulatory functions under various surrounding conditions. Neutrophils induced by IL-23/IL-18 (referred to N(IL-23+IL-18) neutrophils) have a unique gene-expression profile, with highly expressing IL-17, MHC-II, and costimulatory molecules. The adoptive transfer of N(IL-23+IL-18) neutrophils significantly increased the pathogenesis in a renal ischemia-reperfusion injury mouse model. N(IL-23+IL-18) neutrophils directly and efficiently induced allogeneic T cell proliferation in vitro. N(IL-23+IL-18) neutrophils enhanced the syngeneic T cell response to allogeneic antigens in mixed-lymphocyte reaction assays. The adoptive transfer of the donor or host N(IL-23+IL-18) neutrophils significantly enhanced the antidonor antibody production in an allogeneic-skin-transplanted mouse model, accompanied by increased Tfh cells in the spleens. Therefore, the neutrophil subset induced by IL-23/IL-18 promotes tissue injury and antidonor humoral response in the allogeneic transplantation mouse model.
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Affiliation(s)
- Changhong Wu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Jinglin Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Zhaoqi Zhang
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (Z.Z.); (D.W.)
| | - Dong Wei
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (Z.Z.); (D.W.)
| | - Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100045, China; (C.W.); (J.X.); (Y.X.)
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; (Z.Z.); (D.W.)
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen 518055, China
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Knoedler L, Knoedler S, Panayi AC, Lee CAA, Sadigh S, Huelsboemer L, Stoegner VA, Schroeter A, Kern B, Mookerjee V, Lian CG, Tullius SG, Murphy GF, Pomahac B, Kauke-Navarro M. Cellular activation pathways and interaction networks in vascularized composite allotransplantation. Front Immunol 2023; 14:1179355. [PMID: 37266446 PMCID: PMC10230044 DOI: 10.3389/fimmu.2023.1179355] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 04/28/2023] [Indexed: 06/03/2023] Open
Abstract
Vascularized composite allotransplantation (VCA) is an evolving field of reconstructive surgery that has revolutionized the treatment of patients with devastating injuries, including those with limb losses or facial disfigurement. The transplanted units are typically comprised of different tissue types, including skin, mucosa, blood and lymphatic vasculature, muscle, and bone. It is widely accepted that the antigenicity of some VCA components, such as skin, is particularly potent in eliciting a strong recipient rejection response following transplantation. The fine line between tolerance and rejection of the graft is orchestrated by different cell types, including both donor and recipient-derived lymphocytes, macrophages, and other immune and donor-derived tissue cells (e.g., endothelium). Here, we delineate the role of different cell and tissue types during VCA rejection. Rejection of VCA grafts and the necessity of life-long multidrug immunosuppression remains one of the major challenges in this field. This review sheds light on recent developments in decoding the cellular signature of graft rejection in VCA and how these may, ultimately, influence the clinical management of VCA patients by way of novel therapies that target specific cellular processes.
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Affiliation(s)
- Leonard Knoedler
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Samuel Knoedler
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Adriana C. Panayi
- Department of Surgery, Division of Plastic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Department of Hand, Plastic and Reconstructive Surgery, Microsurgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
| | - Catherine A. A. Lee
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
| | - Sam Sadigh
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
| | - Lioba Huelsboemer
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Viola A. Stoegner
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Burn Center, Hannover Medical School, Hannover, Germany
| | - Andreas Schroeter
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Burn Center, Hannover Medical School, Hannover, Germany
- Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Barbara Kern
- Department of Plastic Surgery, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Vikram Mookerjee
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Christine G. Lian
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
| | - Stefan G. Tullius
- Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - George F. Murphy
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
| | - Bohdan Pomahac
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Martin Kauke-Navarro
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
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M2c Macrophages Protect Mice from Adriamycin-Induced Nephropathy by Upregulating CD62L in Tregs. Mediators Inflamm 2022; 2022:1153300. [PMID: 36262548 PMCID: PMC9576407 DOI: 10.1155/2022/1153300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/28/2022] [Accepted: 09/12/2022] [Indexed: 11/17/2022] Open
Abstract
Regulatory T cells (Tregs) and M2c macrophages have been shown to exert potentially synergistic therapeutic effects in animals with adriamycin-induced nephropathy (AN), a model chronic proteinuric renal disease. M2c macrophages may protect against renal injury by promoting an increase in the number of Tregs in the renal draining lymph nodes of AN mice, but how they do so is unclear. In this study, we used an AN mouse model to analyze how M2c macrophages induce the migration of Tregs. Using flow cytometry, we found that M2c macrophages promoted the migration of Tregs from the peripheral blood to the spleen, thymus, kidney, and renal draining lymph nodes. At the same time, M2c macrophages significantly upregulated chemokine receptors and adhesion molecule in Tregs, including CCR4, CCR5, CCR7, CXCR5, and CD62L. Treating AN mice with monoclonal anti-CD62L antibody inhibited the migration of M2c macrophages and Tregs to the spleen, thymus, kidney, and renal draining lymph nodes. Taken together, our results suggest that M2c macrophages upregulate CD62L in Tregs and thereby promote their migration to inflammatory sites, where they exert renoprotective effects. These insights may aid the development of treatments against chronic kidney disease.
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Role for exosomes with self-antigens and immune regulatory molecules in allo- and auto-immunity leading to chronic immune injury following murine kidney transplantation. Transpl Immunol 2022; 75:101702. [PMID: 36038048 DOI: 10.1016/j.trim.2022.101702] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Antibodies against donor human leukocyte antigen are a risk factor for chronic immune injury (CII) following renal transplantation; however, it is often not detectable. The main goal of this study is to gain new insights into the kinetics of exosome release and content in sensitized vs non-sensitized recipients. Towards this, we investigated the role for circulating exosomes with allo and self-antigens as well as immunoregulatory molecules in the development of CII and acute rejection. METHODS Using murine kidney allograft rejection models, we investigated the role of exosomes on immune responses leading to allo- and auto-immunity to self-antigens resulting in rejection. Exosomes were analyzed for kidney self-antigens (Collagen-IV, fibronectin, angiotensin II receptor type 1), and immune-regulatory molecules (PD-L1, CD73) using western blot. Antibodies to donor MHC in serum samples were detected by immunofluorescence, self-antigens by enzyme-linked immunosorbent assay and kidney tissue infiltrating cells were determined by immunohistochemistry. RESULTS BALB/c; H2d to C57BL/6; H2b renal transplantation (BALB/c), resulted in tubulitis and cellular infiltration by day 14, suggestive of acute inflammation, that was self-limiting with functioning graft. This contributed to CII on post-transplant day >100, which was preceded by induction of exosomes with donor and self-antigens leading to antibodies and immune-regulatory molecules. The absence of acute rejection in this allogenic transplant model is likely due to the induction of splenic and, graft-infiltrating CD4 + FoxP3+ T regulatory cells. In contrast, prior sensitization by skin graft followed by kidney transplantation induced antibodies to MHC and self-antigens leading to acute rejection. CONCLUSION We demonstrate a pivotal role for induction of exosomes with immune-regulatory molecules, allo- and auto-immunity to self-antigens leading to chronic immune injury following murine kidney transplantation.
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Thangaraj SS, Thiesson HC, Svenningsen P, Stubbe J, Palarasah Y, Bistrup C, Jensen BL, Mortensen LA. Mineralocorticoid receptor blockade with spironolactone has no direct effect on plasma IL-17A and injury markers in urine from kidney transplant patients. Am J Physiol Renal Physiol 2021; 322:F138-F149. [PMID: 34894724 DOI: 10.1152/ajprenal.00104.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Kidney transplantation is associated with increased risk of cardiovascular morbidity. Interleukin-17A (IL-17A) mediates kidney injury. Aldosterone promotes T-helper-17 (Th-17) lymphocyte differentiation and IL-17A production through the mineralocorticoid receptor (MR). In this exploratory, post-hoc substudy, it was hypothesized that 1-year intervention with the MR antagonist spironolactone lowers IL-17A and related cytokines and reduces epithelial injury in kidney transplant recipients. Plasma and urine samples were obtained from kidney transplant recipients from a double-blind randomized clinical trial testing spironolactone (n=39) versus placebo (n=41). Plasma concentrations of cytokines IFN-γ, IL-17A, TNF-α, IL-6, IL-1β, and IL-10 were determined before and after 1-year treatment. Urine calbindin, clusterin, KIM-1, osteoactivin, TFF3, and VEGF/creatinine ratios were analyzed. Blood pressure and plasma aldosterone concentration at inclusion did not relate to plasma cytokines and injury markers. None of the cytokines changed in plasma after spironolactone intervention. Plasma IL-17A increased in the placebo group. Spironolactone induced an increase in plasma K+ (0.4 ± 0.4 mmol/L). This increase did not correlate with plasma IL-17A or urine calbindin and TFF3 changes. Ongoing treatment at inclusion with angiotensin-converting-enzyme inhibitor and/or angiotensin II receptor blockers was not associated with changed levels of IL-17A and injury markers and had no effect on the response to spironolactone. Urinary calbindin and TFF3 decreased in the spironolactone group with no difference in between-group analyses. In conclusion, irrespective of ongoing ANGII inhibition, spironolactone has no effect on plasma IL-17A and related cytokines or urinary injury markers in kidney transplant recipients.
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Affiliation(s)
- Sai Sindhu Thangaraj
- Department of Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Helle Charlotte Thiesson
- Department of Nephrology, Odense University Hospital, Odense C, Denmark.,Department of Clinical Research, Faculty of Health Science, University of Southern Denmark
| | - Per Svenningsen
- Department of Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Jane Stubbe
- Department of Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Yaseelan Palarasah
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of southern Denmark, Odense C, Denmark
| | - Claus Bistrup
- Department of Nephrology, Odense University Hospital, Odense C, Denmark.,Department of Clinical Research, Faculty of Health Science, University of Southern Denmark
| | - Boye L Jensen
- Department of Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
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11
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Zhu J, Inomata T, Di Zazzo A, Kitazawa K, Okumura Y, Coassin M, Surico PL, Fujio K, Yanagawa A, Miura M, Akasaki Y, Fujimoto K, Nagino K, Midorikawa-Inomata A, Hirosawa K, Kuwahara M, Huang T, Shokirova H, Eguchi A, Murakami A. Role of Immune Cell Diversity and Heterogeneity in Corneal Graft Survival: A Systematic Review and Meta-Analysis. J Clin Med 2021; 10:jcm10204667. [PMID: 34682792 PMCID: PMC8537034 DOI: 10.3390/jcm10204667] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 09/30/2021] [Accepted: 10/08/2021] [Indexed: 12/22/2022] Open
Abstract
Corneal transplantation is one of the most successful forms of solid organ transplantation; however, immune rejection is still a major cause of corneal graft failure. Both innate and adaptive immunity play a significant role in allograft tolerance. Therefore, immune cells, cytokines, and signal-transduction pathways are critical therapeutic targets. In this analysis, we aimed to review the current literature on various immunotherapeutic approaches for corneal-allograft rejection using the PubMed, EMBASE, Web of Science, Cochrane, and China National Knowledge Infrastructure. Retrievable data for meta-analysis were screened and assessed. The review, which evaluated multiple immunotherapeutic approaches to prevent corneal allograft rejection, showed extensive involvement of innate and adaptive immunity components. Understanding the contribution of this immune diversity to the ocular surface is critical for ensuring corneal allograft survival.
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Affiliation(s)
- Jun Zhu
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Ophthalmology, Subei People’s Hospital of Jiangsu Province, Yangzhou 225001, China
| | - Takenori Inomata
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Strategic Operating Room Management and Improvement, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan
- Department of Hospital Administration, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (K.N.); (A.M.-I.); (A.E.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
- Department of Ophthalmology, Faculty of Medicine, Juntendo University, Tokyo 1130033, Japan
- Correspondence: ; Tel.: +81-3-5802-1228
| | - Antonio Di Zazzo
- Ophthalmology Complex Operative Unit, Campus Bio-Medico University Hospital, 00128 Rome, Italy; (A.D.Z.); (M.C.); (P.L.S.)
| | - Koji Kitazawa
- Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto 6020841, Japan;
- Buck Institute for Research on Aging, Novato, CA 94945, USA
| | - Yuichi Okumura
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Strategic Operating Room Management and Improvement, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Marco Coassin
- Ophthalmology Complex Operative Unit, Campus Bio-Medico University Hospital, 00128 Rome, Italy; (A.D.Z.); (M.C.); (P.L.S.)
| | - Pier Luigi Surico
- Ophthalmology Complex Operative Unit, Campus Bio-Medico University Hospital, 00128 Rome, Italy; (A.D.Z.); (M.C.); (P.L.S.)
| | - Kenta Fujio
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Ai Yanagawa
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Maria Miura
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Yasutsugu Akasaki
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Keiichi Fujimoto
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
- Department of Ophthalmology, Faculty of Medicine, Juntendo University, Tokyo 1130033, Japan
| | - Ken Nagino
- Department of Hospital Administration, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (K.N.); (A.M.-I.); (A.E.)
| | - Akie Midorikawa-Inomata
- Department of Hospital Administration, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (K.N.); (A.M.-I.); (A.E.)
| | - Kunihiko Hirosawa
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Mizu Kuwahara
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Tianxiang Huang
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
| | - Hurramhon Shokirova
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
| | - Atsuko Eguchi
- Department of Hospital Administration, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (K.N.); (A.M.-I.); (A.E.)
| | - Akira Murakami
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (J.Z.); (Y.O.); (K.F.); (M.M.); (Y.A.); (K.H.); (M.K.); (T.H.); (H.S.); (A.M.)
- Department of Digital Medicine, Juntendo University Graduate School of Medicine, Tokyo 1130033, Japan; (A.Y.); (K.F.)
- Department of Ophthalmology, Faculty of Medicine, Juntendo University, Tokyo 1130033, Japan
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12
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Hu M, Rogers NM, Li J, Zhang GY, Wang YM, Shaw K, O'Connell PJ, Alexander SI. Antigen Specific Regulatory T Cells in Kidney Transplantation and Other Tolerance Settings. Front Immunol 2021; 12:717594. [PMID: 34512640 PMCID: PMC8428972 DOI: 10.3389/fimmu.2021.717594] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/05/2021] [Indexed: 12/25/2022] Open
Abstract
Kidney transplantation is the most common solid organ transplant and the best current therapy for end-stage kidney failure. However, with standard immunosuppression, most transplants develop chronic dysfunction or fail, much of which is due to chronic immune injury. Tregs are a subset of T cells involved in limiting immune activation and preventing autoimmune disease. These cells offer the potential to provide tolerance or to allow reduction in immunosuppression in kidney transplants. The importance of Tregs in kidney transplantation has been shown in a number of seminal mouse and animal studies, including those with T cell receptors (TCRs) transgenic Tregs (TCR-Tregs) or Chimeric Antigen Receptor (CAR) Tregs (CAR-Tregs) showing that specificity increases the potency of Treg function. Here we outline the animal and human studies and clinical trials directed at using Tregs in kidney transplantation and other tolerance settings and the various modifications to enhance allo-specific Treg function in vivo and in vitro.
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Affiliation(s)
- Min Hu
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Sydney, NSW, Australia.,Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Natasha M Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Jennifer Li
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Geoff Y Zhang
- Centre for Kidney Research, Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Yuan Min Wang
- Centre for Kidney Research, Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Karli Shaw
- Centre for Kidney Research, Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Philip J O'Connell
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Stephen I Alexander
- Centre for Kidney Research, Children's Hospital at Westmead, Sydney, NSW, Australia
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13
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Lassiter R, Merchen TD, Fang X, Wang Y. Protective Role of Kynurenine 3-Monooxygenase in Allograft Rejection and Tubular Injury in Kidney Transplantation. Front Immunol 2021; 12:671025. [PMID: 34305900 PMCID: PMC8293746 DOI: 10.3389/fimmu.2021.671025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 06/11/2021] [Indexed: 11/13/2022] Open
Abstract
Renal tubular epithelial cells (TECs) are the primary targets of ischemia-reperfusion injury (IRI) and rejection by the recipient's immune response in kidney transplantation (KTx). However, the molecular mechanism of rejection and IRI remains to be identified. Our previous study demonstrated that kynurenine 3-monooxygenase (KMO) and kynureninase were reduced in ischemia-reperfusion procedure and further decreased in rejection allografts among mismatched pig KTx. Herein, we reveal that TEC injury in acutely rejection allografts is associated with alterations of Bcl2 family proteins, reduction of tight junction protein 1 (TJP1), and TEC-specific KMO. Three cytokines, IFN γ , TNFα, and IL1β, reported in our previous investigation were identified as triggers of TEC injury by altering the expression of Bcl2, BID, and TJP1. Allograft rejection and TEC injury were always associated with a dramatic reduction of KMO. 3HK and 3HAA, as direct and downstream products of KMO, effectively protected TEC from injury via increasing expression of Bcl-xL and TJP1. Both 3HK and 3HAA further prevented allograft rejection by inhibiting T cell proliferation and up-regulating aryl hydrocarbon receptor expression. Pig KTx with the administration of DNA nanoparticles (DNP) that induce expression of indoleamine 2,3-dioxygenase (IDO) and KMO to increase 3HK/3HAA showed an improvement of allograft rejection as well as murine skin transplant in IDO knockout mice with the injection of 3HK indicated a dramatic reduction of allograft rejection. Taken together, our data provide strong evidence that reduction of KMO in the graft is a key mediator of allograft rejection and loss. KMO can effectively improve allograft outcome by attenuating allograft rejection and maintaining graft barrier function.
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Affiliation(s)
- Randi Lassiter
- Department of Surgery, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Todd D. Merchen
- Department of Surgery, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Xuexiu Fang
- Division of Nephrology, Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Youli Wang
- Division of Nephrology, Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA, United States
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14
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Lin J, Wang H, Liu C, Cheng A, Deng Q, Zhu H, Chen J. Dendritic Cells: Versatile Players in Renal Transplantation. Front Immunol 2021; 12:654540. [PMID: 34093544 PMCID: PMC8170486 DOI: 10.3389/fimmu.2021.654540] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 04/22/2021] [Indexed: 12/30/2022] Open
Abstract
Dendritic cells (DCs) induce and regulate adaptive immunity through migrating and maturing in the kidney. In this procedure, they can adopt different phenotypes—rejection-associated DCs promote acute or chronic injury renal grafts while tolerogenic DCs suppress the overwhelmed inflammation preventing damage to renal functionality. All the subsets interact with effector T cells and regulatory T cells (Tregs) stimulated by the ischemia–reperfusion procedure, although the classification corresponding to different effects remains controversial. Thus, in this review, we discuss the origin, maturation, and pathological effects of DCs in the kidney. Then we summarize the roles of divergent DCs in renal transplantation: taking both positive and negative stages in ischemia–reperfusion injury (IRI), switching phenotypes to induce acute or chronic rejection, and orchestrating surface markers for allograft tolerance via alterations in metabolism. In conclusion, we prospect that multidimensional transcriptomic analysis will revolute researches on renal transplantation by addressing the elusive mononuclear phagocyte classification and providing a holistic view of DC ontogeny and subpopulations.
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Affiliation(s)
- Jinwen Lin
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Disease, Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Hongyi Wang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Chenxi Liu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Ao Cheng
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Qingwei Deng
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Huijuan Zhu
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Disease, Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
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15
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Zhu JQ, Wang J, Li XL, Xu WL, Lv SC, Zhao X, Lang R, He Q. A combination of the percentages of IFN-γ +CD4 +T cells and granzyme B +CD19 +B cells is associated with acute hepatic rejection: a case control study. J Transl Med 2021; 19:187. [PMID: 33933100 PMCID: PMC8088570 DOI: 10.1186/s12967-021-02855-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 04/21/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND T cells and B cells play a key role in alloimmune responses. We aimed to characterize the shift of T cell subsets and B cell subsets during acute hepatic rejection, and further determine whether they could serve as a prognostic marker. METHODS Blood samples together with the clinical data from liver transplant recipients with and without acute hepatic rejection were collected and analyzed as well as from a validation cohort. RESULTS Upon activation the expression of TGF-β and granzyme B in CD19+B cells, and the expression of IL-2 and IFN-γ in CD4+T cells were higher in acute hepatic rejection. However, only the frequencies of granzyme B+CD19+B cells and IFN-γ+CD4+T cells correlated with liver function in addition to with each other. A combination of the two cell subsets as a novel marker could classify rejection versus non-rejection (area under the curve 0.811, p = 0.001) with the cut-off value of 62.93%, which was more sensitive for worse histological changes (p = 0.027). Moreover, the occurrence rate of acute rejection was higher in the group with the novel marker > 62.93% (p = 0.000). The role of the novel marker was further confirmed in a validation cohort, which was identified to be the only significant independent risk factor for acute rejection (odds ratio: 0.923; 95% CI confidence interval: 0.885-0.964; p = 0.000). CONCLUSIONS A combination of the percentages of IFN-γ+CD4+T cells and granzyme B+CD19+B cells can distinguish rejection from non-rejection, which can be used as a potential prognostic marker for acute rejection in liver transplant recipients.
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Affiliation(s)
- Ji-Qiao Zhu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Jing Wang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Xian-Liang Li
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Wen-Li Xu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Shao-cheng Lv
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Xin Zhao
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Ren Lang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020 China
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16
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Zhuang Q, Cai H, Cao Q, Li Z, Liu S, Ming Y. Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation. Front Immunol 2020; 11:552988. [PMID: 33123131 PMCID: PMC7573100 DOI: 10.3389/fimmu.2020.552988] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 08/12/2020] [Indexed: 12/19/2022] Open
Abstract
Over a half century, organ transplantation has become an effective method for the treatment of end-stage visceral diseases. Although the application of immunosuppressants (IS) minimizes the rate of allograft rejection, the common use of IS bring many adverse effects to transplant patients. Moreover, true transplant tolerance is very rare in clinical practice. Dendritic cells (DCs) are thought to be the most potent antigen-presenting cells, which makes a bridge between innate and adaptive immunity. Among their subsets, a small portion of DCs with immunoregulatory function was known as tolerogenic DC (Tol-DC). Previous reports demonstrated the ability of adoptively transferred Tol-DC to approach transplant tolerance in animal models. In this study, we summarized the properties, ex vivo generation, metabolism, and clinical attempts of Tol-DC. Tol-DC is expected to become a substitute for IS to enable patients to achieve immune tolerance in the future.
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Affiliation(s)
- Quan Zhuang
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China.,Research Center of National Health Ministry on Transplantation Medicine, Changsha, China
| | - Haozheng Cai
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China
| | - Qingtai Cao
- Hunan Normal University School of Medicine, Changsha, China
| | - Zixin Li
- Hunan Normal University School of Medicine, Changsha, China
| | - Shu Liu
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China.,Research Center of National Health Ministry on Transplantation Medicine, Changsha, China
| | - Yingzi Ming
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China.,Research Center of National Health Ministry on Transplantation Medicine, Changsha, China
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17
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Wu H, Singer J, Kwan TK, Loh YW, Wang C, Tan J, Li YJ, Lai SWC, Macia L, Alexander SI, Chadban SJ. Gut Microbial Metabolites Induce Donor-Specific Tolerance of Kidney Allografts through Induction of T Regulatory Cells by Short-Chain Fatty Acids. J Am Soc Nephrol 2020; 31:1445-1461. [PMID: 32482686 DOI: 10.1681/asn.2019080852] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 03/22/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Short-chain fatty acids derived from gut microbial fermentation of dietary fiber have been shown to suppress autoimmunity through mechanisms that include enhanced regulation by T regulatory cells (Tregs). METHODS Using a murine kidney transplantation model, we examined the effects on alloimmunity of a high-fiber diet or supplementation with the short-chain fatty acid acetate. Kidney transplants were performed from BALB/c(H2d) to B6(H2b) mice as allografts in wild-type and recipient mice lacking the G protein-coupled receptor GPR43 (the metabolite-sensing receptor of acetate). Allograft mice received normal chow, a high-fiber diet, or normal chow supplemented with sodium acetate. We assessed rejection at days 14 (acute) and 100 (chronic), and used 16S rRNA sequencing to determine gut microbiota composition pretransplantation and post-transplantation. RESULTS Wild-type mice fed normal chow exhibited dysbiosis after receiving a kidney allograft but not an isograft, despite the avoidance of antibiotics and immunosuppression for the latter. A high-fiber diet prevented dysbiosis in allograft recipients, who demonstrated prolonged survival and reduced evidence of rejection compared with mice fed normal chow. Allograft mice receiving supplemental sodium acetate exhibited similar protection from rejection, and subsequently demonstrated donor-specific tolerance. Depletion of CD25+ Tregs or absence of the short-chain fatty acid receptor GPR43 abolished this survival advantage. CONCLUSIONS Manipulation of the microbiome by a high-fiber diet or supplementation with sodium acetate modified alloimmunity in a kidney transplant model, generating tolerance dependent on Tregs and GPR43. Diet-based therapy to induce changes in the gut microbiome can alter systemic alloimmunity in mice, in part through the production of short-chain fatty acids leading to Treg cell development, and merits study as a potential clinical strategy to facilitate transplant acceptance.
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Affiliation(s)
- Huiling Wu
- Kidney Node Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia .,Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.,Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Julian Singer
- Kidney Node Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia.,Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Tony K Kwan
- Kidney Node Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia.,Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Yik Wen Loh
- Kidney Node Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia.,Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Chuanmin Wang
- Kidney Node Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia.,Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Jian Tan
- Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.,Nutritional Immunometabolism Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia
| | - Yan J Li
- Kidney Node Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia
| | - Sum Wing Christina Lai
- Kidney Node Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia
| | - Laurence Macia
- Nutritional Immunometabolism Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia.,School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Stephen I Alexander
- Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.,Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - Steven J Chadban
- Kidney Node Laboratory, The Charles Perkins Centre, Camperdown, New South Wales, Australia.,Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.,Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
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Matsunaga T, Azuma H, Tullius SG. Immunosuppression in vascularized composite allotransplant: the search for an effective and safe treatment continues. Transpl Int 2020; 33:1291-1293. [PMID: 32348589 DOI: 10.1111/tri.13629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 04/24/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Tomohisa Matsunaga
- Division of Transplant Surgery, Department of Surgery, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.,Department of Urology, Osaka Medical College, Osaka, Japan
| | - Haruhito Azuma
- Department of Urology, Osaka Medical College, Osaka, Japan
| | - Stefan G Tullius
- Division of Transplant Surgery, Department of Surgery, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
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19
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Crepeau RL, Ford ML. Programmed T cell differentiation: Implications for transplantation. Cell Immunol 2020; 351:104099. [PMID: 32247511 DOI: 10.1016/j.cellimm.2020.104099] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/27/2020] [Accepted: 03/27/2020] [Indexed: 12/27/2022]
Abstract
While T cells play a critical role in protective immunity against infection, they are also responsible for graft rejection in the setting of transplantation. T cell differentiation is regulated by both intrinsic transcriptional pathways as well as extrinsic factors such as antigen encounter and the cytokine milieu. Herein, we review recent discoveries in the transcriptional regulation of T cell differentiation and their impact on the field of transplantation. Recent studies uncovering context-dependent differentiation programs that differ in the setting of infection or transplantation will also be discussed. Understanding the key transcriptional pathways that underlie T cell responses in transplantation has important clinical implications, including development of novel therapeutic agents to mitigate graft rejection.
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Affiliation(s)
- Rebecca L Crepeau
- Emory Transplant Center, Department of Surgery, Emory University, 101 Woodruff Circle, Suite 5208, Atlanta, GA 30322, United States
| | - Mandy L Ford
- Emory Transplant Center, Department of Surgery, Emory University, 101 Woodruff Circle, Suite 5208, Atlanta, GA 30322, United States.
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20
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Feng Y, Han Z, Feng Z, Wang B, Cheng H, Yang L, Li Y, Gu B, Li X, Li Y, Li Y, Wang C, Chen H. Approaching treatment for immunological rejection of living-donor liver transplantation in rats. BMC Gastroenterol 2020; 20:7. [PMID: 31931737 PMCID: PMC6956502 DOI: 10.1186/s12876-019-1130-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 11/27/2019] [Indexed: 01/10/2023] Open
Abstract
Background The anti-immunological rejection therapy for small-for-size syndrome (SFSS) after live donor liver transplantation (LDLT) play a central role in keeping graft survival. The hepatocyte number and grafts function has undergone real-time changes with the proliferation and apoptosis of the grafts after reperfusion. Lacking an accurate and effective treatment regiments or indicators to guide the use of immunosuppressive drugs in SFS liver transplantation has made immunotherapy after SFS liver transplantation an urgent problem to be solved. Herein, we established small-for-size (SFS) and normal size liver transplantation model in rats to explore the effective indicators in guiding immunotherapy, to find an effective way for overcoming SFSS. Methods Lewis rats (donors) and BN rats (recipients) were used to mimic allograft liver transplantation and treated with tacrolimus. Local graft immune response was analyzed through haematoxylin and eosin and immunohistochemistry. Flow cytometry was used to assess the overall immune status of recipient. The pharmacokinetics mechanism of immunosuppressive drugs was explored through detecting CYP3A2 expression at mRNA level and protein levels. Results The results showed the local immune reaction of SFS grafts and systemic immune responses of recipient were significantly increased compared with those in normal size grafts and their recipient at four days after liver transplantation. Regression equation was used to regulate the tacrolimus dose which not only controlled tacrolimus serum concentration effectively but alleviated liver damage and improved survival rate. Conclusions This study showed that AST level and tacrolimus serum concentrations are effective indicators in guiding immunotherapy. Regression equation (TD = − 0.494TC-0.0035AST + 260.487) based on AST and tacrolimus serum concentration can be used as a reference for adjustment of immunotherapy after SFS liver transplantation, which is applicable in clinical practice.
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Affiliation(s)
- Yanhu Feng
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Zhijian Han
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Zedong Feng
- Medical School of Lanzhou University, Lanzhou, 730030, China
| | - Bofang Wang
- Medical School of Lanzhou University, Lanzhou, 730030, China
| | - Huijuan Cheng
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Luxi Yang
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Yangbing Li
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Baohong Gu
- Medical School of Lanzhou University, Lanzhou, 730030, China
| | - Xuemei Li
- Medical School of Lanzhou University, Lanzhou, 730030, China
| | - Yahao Li
- Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Yumin Li
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, 730030, China. .,Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China.
| | - Chen Wang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China.
| | - Hao Chen
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, 730030, China. .,Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China.
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21
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Wu XS, Lu XL, Wu J, Ma M, Yu J, Zhang ZY. Tocilizumab promotes corneal allograft survival in rats by modulating Treg-Th17 balance. Int J Ophthalmol 2019; 12:1823-1831. [PMID: 31850163 DOI: 10.18240/ijo.2019.12.02] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 06/27/2019] [Indexed: 02/08/2023] Open
Abstract
AIM To examine the therapeutic effects of tocilizumab on experimental corneal transplantation and its effect on Treg/Th17 balance. METHODS Allograft corneal graft was performed between host Sprague Dawley and Wistar donor rats. The rats were randomly divided into four groups: normal, autograft, allograft, and allograft treated with tocilizumab. Kaplan-Meier was performed to draw the survival curve. The protein levels of interleukin-17A (IL-17A), vascular endothelial growth factor (VEGF), and forkhead box protein 3 (Foxp3) were measured by immunohistochemistry. The mRNA levels of IL-17A, VEGF, retinoid-related orphan receptor gammat (RORγt), interleukin-6 (IL-6) and Foxp3 were detected by reverse transcription real-time polymerase chain reaction (RT-PCR). The Treg and Th17 cells were investigated by flow cytometry. RESULTS The survival time of tocilizumab group was (24±1.27d) longer than that of allograft group (10±0.55d). Moreover, immunohistochemical examination revealed that IL-17A and VEGF protein levels in the allograft group were significantly higher than that of tocilizumab group (P<0.01), while Foxp3 levels in the allograft group was significantly lower than that of the tocilizumab treated group (P<0.001). Flow cytometry showed that the number of Th17 cells in allograft group was significantly higher than that in tocilizumab group (P<0.001). Meanwhile, the number of Tregs was significantly lower than in tocilizumab group (P<0.001). Simultaneously, Foxp3 mRNA expression level in corneal tissues of tocilizumab treated group was significantly higher than other groups (P<0.001). CONCLUSION These findings suggest that tocilizumab may promote corneal allograft survival, possibly by modulating Treg-Th17 balance.
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Affiliation(s)
- Xiao-Song Wu
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xiao-Li Lu
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Jing Wu
- Department of Huiqiao Building, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Ming Ma
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Jian Yu
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Zhen-Yu Zhang
- Guangdong Women And Children Hospital, Guangzhou 511400, Guangdong Province, China
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22
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Cytokine Profiles in Children After Pediatric Kidney Transplantation With Acute Cellular Compared to Chronic Antibody-mediated Rejection and Stable Patients: A Pilot Study. Transplant Direct 2019; 5:e501. [PMID: 31773054 PMCID: PMC6831124 DOI: 10.1097/txd.0000000000000943] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/17/2019] [Accepted: 08/19/2019] [Indexed: 12/28/2022] Open
Abstract
Different patterns of plasma cytokines can be expected in the case of chronic active-antibody-mediated (cAMR) and acute cellular rejection (AR) after kidney transplantation (KTx).
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23
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Singh A, Ramachandran S, Graham ML, Daneshmandi S, Heller D, Suarez-Pinzon WL, Balamurugan AN, Ansite JD, Wilhelm JJ, Yang A, Zhang Y, Palani NP, Abrahante JE, Burlak C, Miller SD, Luo X, Hering BJ. Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes. Nat Commun 2019; 10:3495. [PMID: 31375697 PMCID: PMC6677762 DOI: 10.1038/s41467-019-11338-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 07/09/2019] [Indexed: 02/06/2023] Open
Abstract
Immune tolerance to allografts has been pursued for decades as an important goal in transplantation. Administration of apoptotic donor splenocytes effectively induces antigen-specific tolerance to allografts in murine studies. Here we show that two peritransplant infusions of apoptotic donor leukocytes under short-term immunotherapy with antagonistic anti-CD40 antibody 2C10R4, rapamycin, soluble tumor necrosis factor receptor and anti-interleukin 6 receptor antibody induce long-term (≥1 year) tolerance to islet allografts in 5 of 5 nonsensitized, MHC class I-disparate, and one MHC class II DRB allele-matched rhesus macaques. Tolerance in our preclinical model is associated with a regulatory network, involving antigen-specific Tr1 cells exhibiting a distinct transcriptome and indirect specificity for matched MHC class II and mismatched class I peptides. Apoptotic donor leukocyte infusions warrant continued investigation as a cellular, nonchimeric and translatable method for inducing antigen-specific tolerance in transplantation. Injection of donor apoptotic cells induces graft tolerance in mice. Here the authors combine this approach with short immunosuppressive therapy to achieve long-term tolerance to allogeneic islets and restoration of normoglycemia in diabetic nonhuman primates, and delineate cellular and molecular correlates of tolerance induction.
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Affiliation(s)
- Amar Singh
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Sabarinathan Ramachandran
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Melanie L Graham
- Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Saeed Daneshmandi
- Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - David Heller
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Wilma Lucia Suarez-Pinzon
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Appakalai N Balamurugan
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA.,Center for Cellular Transplantation, Cardiovascular Innovation Institute, Department of Surgery, University of Louisville, Louisville, KY, 40202, USA
| | - Jeffrey D Ansite
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Joshua J Wilhelm
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Amy Yang
- Biostatistics Collaboration Center, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Ying Zhang
- Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Nagendra P Palani
- University of Minnesota Genomics Center, Minneapolis, MN, 55455, USA
| | - Juan E Abrahante
- University of Minnesota Informatics Institute, Minneapolis, MN, 55455, USA
| | - Christopher Burlak
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA
| | - Stephen D Miller
- Department of Microbiology-Immunology and Interdepartmental Immunology Center, Northwestern University, Chicago, IL, 60611, USA.
| | - Xunrong Luo
- Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. .,Biostatistics Collaboration Center, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. .,Duke Transplant Center, Department of Medicine, Duke University School of Medicine, Durham, NC, 27710, USA.
| | - Bernhard J Hering
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA.
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24
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Abstract
BACKGROUND T cell-mediated graft rejection is mostly correlated with potent Th1 responses. However, because IFNγ mice reject their graft as efficiently as wild-type (WT) mice, the exact contribution of IFNγ and its transcription factor T-bet remains a matter of debate. Here, we address this question in the context of pancreatic islet allograft to better inform the molecular pathways that hampers islet survival in vivo. METHODS Pancreatic islets from BALB/c mice were transplanted in WT, IFNγ, or T-bet C57BL/6 mice. Graft survival and the induction of effector and cytotoxic T-cell responses were monitored. RESULTS Rejection of fully mismatched islet allografts correlated with high expression of both IFNγ and T-bet in WT recipients. However, allogeneic islets were permanently accepted in T-bet mice, in contrast to IFNγ hosts. Long-term survival correlated with decreased CD4 and CD8 T-cell infiltrates, drastically reduced donor-specific IFNγ and tumor necrosis factor tumor necrosis factor α responses and very low expression of the cytotoxic markers granzyme B, perforin, and FasLigand. In addition, in vitro and in vivo data pointed to an increased susceptibility of T-bet CD8 T cell to apoptosis. These observations were not reported in IFNγ mice, which have set up compensatory effector mechanisms comprising an increased expression of the transcription factor Eomes and cytolytic molecules as well as tumor necrosis factor α-mediated but not IL-4 nor IL-17-mediated allogeneic responses. CONCLUSIONS Anti-islet T-cell responses require T-bet but not IFNγ-dependent programs. Our results provide new clues on the mechanisms dictating islet rejection and may help refine the therapeutic/immunosuppressive regimens applied in diabetic patients receiving islets or pancreas allografts.
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25
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Domanski L, Kłoda K, Patrzyk M, Wisniewska M, Safranow K, Sienko J, Sulikowski T, Staniszewska M, Pawlik A. IL17A and IL17F genes polymorphisms are associated with histopathological changes in transplanted kidney. BMC Nephrol 2019; 20:124. [PMID: 30961540 PMCID: PMC6454731 DOI: 10.1186/s12882-019-1308-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 03/21/2019] [Indexed: 11/10/2022] Open
Abstract
Background Interleukin 17 is a proinflammatory cytokine involved in immune response after allograft transplantation. IL-17 family of proinflammatory cytokines includes IL-17A and IL-17F. Previous studies have demonstrated that the rs2275913 IL17A and the rs11465553 IL17F gene polymorphism are associated with kidney allograft function. Because of the association between these polymorphisms and post-transplant immune response, we assume that these single nucleotide polymorphisms may affect morphological structure of transplanted kidney. The aim of this study was to examine the association of rs2275913 IL17A and rs2397084, rs11465553 and rs763780 IL17F gene polymorphisms with histopathological changes in transplanted kidney biopsies such as: glomerulitis, tubulitis, arteritis, cell infilitration and fibrosis. Methods The study enrolled 82 patients after renal graft transplantation in whom a kidney biopsy was performed because of impaired graft function. The rs2397084 T > C (Glu126Gly), rs11465553 G > A (Val155Ile) and rs763780 T > C (His167Arg) polymorphisms within the IL17F gene and the rs2275913 A > G (− 197 A > G) polymorphism within the IL17A gene promoter were genotyped using TaqMan genotyping assays on a 7500 FAST Real-Time PCR System (Applied Biosystems, USA). Results There was a significant association between the rs2275913 IL17A gene polymorphism and the grade of tubulitis, which was more severe among patients with the A allele, compared to recipients with the GG genotype (GG vs. AG + AA, P = 0.02), and with the grade of arteriolar hyaline thickening and mesangial matrix increase, which were more severe among patients with the G allele compared to recipients with the AA genotype (AA vs. AG + GG, P = 0.01 and P = 0.04, respectively). Tubular atrophy and interstitial fibrosis were more severe among individuals with the C allele at the rs763780 IL17F gene polymorphism (TT vs. TC, P = 0.09 and P = 0.017, respectively). However, it should be taken into account that the statistical significance was achieved without correction for multiple testing, and no significant association would remain significant after such correction. Conclusions The results of this study may suggest a possible association between the rs2275913 IL17A and rs2275913 IL17A gene polymorphisms and some histopathological changes in transplanted kidney biopsies. Electronic supplementary material The online version of this article (10.1186/s12882-019-1308-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Leszek Domanski
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Karolina Kłoda
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Maciej Patrzyk
- Department of Surgery, University Medical Center Greifswald, Greifswald, Germany
| | - Magda Wisniewska
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Krzysztof Safranow
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Jerzy Sienko
- Department of Surgery, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Tadeusz Sulikowski
- Department of Surgery, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Marzena Staniszewska
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72, 70-111, Szczecin, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72, 70-111, Szczecin, Poland.
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26
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Abstract
The role of the pro-inflammatory cytokine IL-17 in the pathogenesis of numerous inflammatory disorders is well-documented, but conflicting results are reported for its role in diabetic nephropathy. Here we examined the role of IL-17 signalling in a model of streptozotocin-induced diabetic nephropathy through IL-17 knockout mice, administration of neutralising monoclonal anti-IL-17 antibody and in vitro examination of gene expression of renal tubular cells and podocytes under high glucose conditions with or without recombinant IL-17. IL-17 deficient mice were protected against progression of diabetic nephropathy, exhibiting reduced albuminuria, glomerular damage, macrophage accumulation and renal fibrosis at 12 weeks and 24 weeks. Administration of anti-IL-17 monoclonal antibody to diabetic wild-type mice was similarly protective. IL-17 deficiency also attenuated up-regulation of pro-inflammatory and pro-fibrotic genes including IL-6, TNF-α, CCL2, CXCL10 and TGF-β in diabetic kidneys. In vitro co-stimulation with recombinant IL-17 and high glucose were synergistic in increasing the expression of pro-inflammatory genes in both cultured renal tubular cells and podocytes. We conclude that absence of IL-17 signalling is protective against streptozotocin-induced diabetic nephropathy, thus implying a pro-inflammatory role of IL-17 in its pathogenesis. Targeting the IL-17 axis may represent a novel therapeutic approach in the treatment of this disorder.
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27
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Zhao Y, Cooper DKC, Wang H, Chen P, He C, Cai Z, Mou L, Luan S, Gao H. Potential pathological role of pro-inflammatory cytokines (IL-6, TNF-α, and IL-17) in xenotransplantation. Xenotransplantation 2019; 26:e12502. [PMID: 30770591 DOI: 10.1111/xen.12502] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 12/04/2018] [Accepted: 01/18/2019] [Indexed: 12/15/2022]
Abstract
The major limitation of organ transplantation is the shortage of available organs from deceased human donors which leads to the deaths of thousands of patients each year. Xenotransplantation is considered to be an effective way to resolve the problem. Immune rejection and coagulation dysfunction are two major hurdles for the successful survival of pig xenografts in primate recipients. Pro-inflammatory cytokines, such as IL-6, TNF-α, and IL-17, play important roles in many diseases and in allotransplantation. However, the pathological roles of these pro-inflammatory cytokines in xenotransplantation remain unclear. Here, we briefly review the signaling transduction and expression regulation of IL-6, TNF-α, and IL-17 and evaluate their potential pathological roles in in vitro and in vivo models of xenotransplantation. We found that IL-6, TNF-α, and IL-17 were induced in most in vitro or in vivo xenotransplantation model. Blockade of these cytokines using gene modification, antibody, or inhibitor had different effects in xenotransplantation. Inhibition of IL-6 signaling with tocilizumab decreased CRP but did not increase xenograft survival. The one possible reason is that tocilizumab can not suppress IL-6 signaling in porcine cells or organs. Other drugs which inhibit IL-6 signaling need to be investigated in xenotransplantation model. Inhibition of TNF-α was beneficial for the survival of xenografts in pig-to-mouse, rat, or NHP models. Blockade of IL-17 using a neutralizing antibody also increased xenograft survival in several animal models. However, the role of IL-17 in the pig-to-NHP xenotransplantation model remains unclear and needs to be further investigated. Moreover, blockade of TNF-α and IL-6 together has got a better effect in pig-to-baboon kidney xenotransplantation. Blockade two or even more cytokines together might get better effect in suppressing xenograft rejection. Better understanding the role of these cytokines in xenotransplantation will be beneficial for choosing better immunosuppressive strategy or producing genetic modification pig.
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Affiliation(s)
- Yanli Zhao
- Department of Nephrology, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, Shenzhen, China.,Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, Shenzhen, China.,Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, Shenzhen, China
| | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Huiyun Wang
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, Shenzhen, China
| | - Pengfei Chen
- Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, Shenzhen, China
| | - Chen He
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, Shenzhen, China
| | - Zhiming Cai
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, Shenzhen, China
| | - Lisha Mou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, Shenzhen, China
| | - Shaodong Luan
- Department of Nephrology, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, Shenzhen, China
| | - Hanchao Gao
- Department of Nephrology, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, Shenzhen, China.,Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen University School of Medicine, Shenzhen, China.,Department of Medical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University Affiliated Longhua District Central Hospital, Shenzhen, China
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28
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Liu Y, Wang K, Liang X, Li Y, Zhang Y, Zhang C, Wei H, Luo R, Ge S, Xu G. Complement C3 Produced by Macrophages Promotes Renal Fibrosis via IL-17A Secretion. Front Immunol 2018; 9:2385. [PMID: 30405606 PMCID: PMC6204358 DOI: 10.3389/fimmu.2018.02385] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 09/26/2018] [Indexed: 12/21/2022] Open
Abstract
Complement synthesis in cells of origin is strongly linked to the pathogenesis and progression of renal disease. Multiple studies have examined local C3 synthesis in renal disease and elucidated the contribution of local cellular sources, but the contribution of infiltrating inflammatory cells remains unclear. We investigate the relationships among C3, macrophages and Th17 cells, which are involved in interstitial fibrosis. Here, we report that increased local C3 expression, mainly by monocyte/macrophages, was detected in renal biopsy specimens and was correlated with the severity of renal fibrosis (RF) and indexes of renal function. In mouse models of UUO (unilateral ureteral obstruction), we found that local C3 was constitutively expressed throughout the kidney in the interstitium, from which it was released by F4/80+macrophages. After the depletion of macrophages using clodronate, mice lacking macrophages exhibited reductions in C3 expression and renal tubulointerstitial fibrosis. Blocking C3 expression with a C3 and C3aR inhibitor provided similar protection against renal tubulointerstitial fibrosis. These protective effects were associated with reduced pro-inflammatory cytokines, renal recruitment of inflammatory cells, and the Th17 response. in vitro, recombinant C3a significantly enhanced T cell proliferation and IL-17A expression, which was mediated through phosphorylation of ERK, STAT3, and STAT5 and activation of NF-kB in T cells. More importantly, blockade of C3a by a C3aR inhibitor drastically suppressed IL-17A expression in C3a-stimulated T cells. We propose that local C3 secretion by macrophages leads to IL-17A-mediated inflammatory cell infiltration into the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the C3a/C3aR pathway is a novel therapeutic approach for obstructive nephropathy.
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Affiliation(s)
- Yanyan Liu
- Division of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Wang
- Division of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinjun Liang
- Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yueqiang Li
- Division of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Zhang
- Division of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunxiu Zhang
- Division of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haotian Wei
- Division of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ran Luo
- Division of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuwang Ge
- Division of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gang Xu
- Division of Internal Medicine, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Jane-Wit D, Fang C, Goldstein DR. Innate immune mechanisms in transplant allograft vasculopathy. Curr Opin Organ Transplant 2017; 21:253-7. [PMID: 27077602 DOI: 10.1097/mot.0000000000000314] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW Allograft vasculopathy is the leading cause of late allograft loss following solid organ transplantation. Ischemia reperfusion injury and donor-specific antibody-induced complement activation confer heightened risk for allograft vasculopathy via numerous innate immune mechanisms, including MyD88, high-mobility group box 1 (HMGB1), and complement-induced noncanonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. RECENT FINDINGS The role of MyD88, a signal adaptor downstream of the Toll-like receptors (TLR), has been defined in an experimental heart transplant model, which demonstrated that recipient MyD88 enhanced allograft vasculopathy. Importantly, triggering receptor on myeloid receptor 1, a MyD88 amplifying signal, was present in rejecting human cardiac transplant biopsies and enhanced the development of allograft vasculopathy in mice. HMGB1, a nuclear protein that activates Toll-like receptors, also enhanced the development of allograft vasculopathy. Complement activation elicits assembly of membrane attack complexes on endothelial cells which activate noncanonical NF-κB signaling, a novel complement effector pathway that induces proinflammatory genes and potentiates endothelial cell-mediated alloimmune T-cell activation, processes which enhance allograft vasculopathy. SUMMARY Innate immune mediators, including HMGB1, MyD88, and noncanonical NF-κB signaling via complement activation contribute to allograft vasculopathy. These pathways represent potential therapeutic targets to reduce allograft vasculopathy after solid organ transplantation.
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Affiliation(s)
- Dan Jane-Wit
- aDepartment of Cardiovascular Medicine bDepartment of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA
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Suppressive Effect of 1α,25-Dihydroxyvitamin D3 on Th17-Immune Responses in Kidney Transplant Recipients With Tacrolimus-Based Immunosuppression. Transplantation 2017; 101:1711-1719. [PMID: 28107277 DOI: 10.1097/tp.0000000000001516] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND The aim of this study was to investigate whether 1α,25-dihydroxyvitamin D3 can regulate Th17-related immune responses in kidney transplant recipients (KTRs) being treated with tacrolimus (Tac)-based immunosuppression. METHODS First, we evaluated the effect of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on Th17-immune responses in an in vitro study using peripheral blood mononuclear cells (PBMCs) from healthy volunteers or KTRs. Next, we investigated mammalian target of rapamycin/STAT3 signaling as a mechanism by which 1,25(OH)2D3 exerted its effect on T cells using the Jurkat cell line. Third, we investigated Th17-cytokine levels or Th17 cell percentage in PBMCs according to the serum 25-hydroxyvitamin D (25(OH)D) level in 81 KTRs, and we performed a prospective study to assess whether 1,25(OH)2D3 (calcitriol) treatment decreased Th17 cytokine levels (IL-17, IL-22) in 42 KTRs. RESULTS In the in vitro study, we observed that the addition of 1,25(OH)2D3 to Tac significantly inhibited the appearance of IL-17-positive cells in culture. The expression of IL-17 and IL-22 messenger RNA in PBMCs was also decreased by the addition of 1,25(OH)2D3. In the Jurkat cell line, the mTOR/STAT3 pathway was further downregulated with the addition of 1,25(OH)2D3 to Tac. In the 81 KTRs, the 25(OH)D level was inversely correlated with the Th17 cytokine levels or the proportion of Th17 cell out of CD4 T cells. Treatment with calcitriol for 6 months significantly decreased Th17 cytokine levels compared with the baseline values in another 42 KTRs. CONCLUSIONS Treatment with 1,25(OH)2D3 may have immunologic benefits by effectively suppressing the Th17-related immune responses in KTRs on Tac-based immunosuppression.
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Gupta PK, Wagner SR, Wu Q, Shilling RA. IL-17A Blockade Attenuates Obliterative Bronchiolitis and IFN-γ Cellular Immune Response in Lung Allografts. Am J Respir Cell Mol Biol 2017; 56:708-715. [PMID: 28118023 DOI: 10.1165/rcmb.2016-0154oc] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Obliterative bronchiolitis (OB), characterized by fibrous obliteration of the small airways, is a major impediment to long-term survival in lung allograft recipients. We found previously that IL-17A is produced primarily by CD4+ T cells and γδ T cells after lung transplant in a mouse model of orthotopic lung transplant. The absence of either subset of T cells was compensated for by expansion of the other subset, which suggested that systemic blockade of IL-17A was necessary. To determine the specific role of IL-17A in the development of OB, we treated lung allograft recipients with an IL-17A antagonistic antibody. After IL-17A blockade, the incidence of OB was significantly reduced in lung allografts. IL-17A blockade also significantly attenuated the severity of acute rejection and overall lung fibrosis. The decreased OB incidence was associated with reduced lymphocyte recruitment, particularly CD8+ T cells and other IFN-γ-producing lymphocytes, to the lung allograft. Interestingly, IL-17A blockade led to an increase in the frequency of IL-17A-producing T-helper cell type 17 cells and γδ T cells in lung allografts, suggesting that IL-17A is a negative regulator of these T cells. Our data suggest that blocking IL-17A after lung transplant reduces the overall IFN-γ-mediated lymphocyte response and decreases the development of OB.
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Affiliation(s)
- Pawan Kumar Gupta
- 1 Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, and
| | - Sarah R Wagner
- 1 Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, and
| | - Qiang Wu
- 1 Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, and
| | - Rebecca A Shilling
- 1 Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, and.,2 Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois
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Li Y, Huang Z, Yan R, Liu M, Bai Y, Liang G, Zhang X, Hu X, Chen J, Huang C, Liu B, Luo G, Wu J, He W. Vγ4 γδ T Cells Provide an Early Source of IL-17A and Accelerate Skin Graft Rejection. J Invest Dermatol 2017; 137:2513-2522. [PMID: 28733202 DOI: 10.1016/j.jid.2017.03.043] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 03/02/2017] [Accepted: 03/06/2017] [Indexed: 01/12/2023]
Abstract
Activated γδ T cells have been shown to accelerate allograft rejection. However, the precise role of skin-resident γδ T cells and their subsets-Vγ5 (epidermis), Vγ1, and Vγ4 (dermis)-in skin graft rejection have not been identified. Here, using a male to female skin transplantation model, we demonstrated that Vγ4 T cells, rather than Vγ1 or Vγ5 T cells, accelerated skin graft rejection and that IL-17A was essential for Vγ4 T-cell-mediated skin graft rejection. Moreover, we found that Vγ4 T cells were required for early IL-17A production in the transplanted area, both in skin grafts and in the host epidermis around grafts. Additionally, the chemokine (C-C motif) ligand 20-chemokine receptor 6 pathway was essential for recruitment of Vγ4 T cells to the transplantation area, whereas both IL-1β and IL-23 induced IL-17A production from infiltrating cells. Lastly, Vγ4 T-cell-derived IL-17A promoted the accumulation of mature dendritic cells in draining lymph nodes to subsequently regulate αβ T-cell function after skin graft transplantation. Taken together, our data reveal that Vγ4 T cells accelerate skin graft rejection by providing an early source of IL-17A.
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Affiliation(s)
- Yashu Li
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Zhenggen Huang
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Rongshuai Yan
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Meixi Liu
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Yang Bai
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Guangping Liang
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Xiaorong Zhang
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Xiaohong Hu
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Jian Chen
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Chibing Huang
- Department of Urology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
| | - Baoyi Liu
- Department of Orthopedic, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Gaoxing Luo
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China.
| | - Jun Wu
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China.
| | - Weifeng He
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Disease Proteomics, Chongqing, China.
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Ezzelarab M, Raich-Regue D, Lu L, Zahorchak A, Perez-Gutierrez A, Humar A, Wijkstrom M, Minervini M, Wiseman R, Cooper D, Morelli A, Thomson A. Renal Allograft Survival in Nonhuman Primates Infused With Donor Antigen-Pulsed Autologous Regulatory Dendritic Cells. Am J Transplant 2017; 17:1476-1489. [PMID: 28009481 PMCID: PMC5444942 DOI: 10.1111/ajt.14182] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 11/30/2016] [Accepted: 12/15/2016] [Indexed: 01/25/2023]
Abstract
Systemic administration of autologous regulatory dendritic cells (DCreg; unpulsed or pulsed with donor antigen [Ag]), prolongs allograft survival and promotes transplant tolerance in rodents. Here, we demonstrate that nonhuman primate (NHP) monocyte-derived DCreg preloaded with cell membrane vesicles from allogeneic peripheral blood mononuclear cells induce T cell hyporesponsiveness to donor alloantigen (alloAg) in vitro. These donor alloAg-pulsed autologous DCreg (1.4-3.6 × 106 /kg) were administered intravenously, 1 day before MHC-mismatched renal transplantation to rhesus monkeys treated with costimulation blockade (cytotoxic T lymphocyte Ag 4 immunoglobulin [CTLA4] Ig) and tapered rapamycin. Prolongation of graft median survival time from 39.5 days (no DCreg infusion; n = 6 historical controls) and 29 days with control unpulsed DCreg (n = 2), to 56 days with donor Ag-pulsed DCreg (n = 5) was associated with evidence of modulated host CD4+ and CD8+ T cell responses to donor Ag and attenuation of systemic IL-17 production. Circulating anti-donor antibody (Ab) was not detected until CTLA4 Ig withdrawal. One monkey treated with donor Ag-pulsed DCreg rejected its graft in association with progressively elevated anti-donor Ab, 525 days posttransplant (160 days after withdrawal of immunosuppression). These findings indicate a modest but not statistically significant beneficial effect of donor Ag-pulsed autologous DCreg infusion on NHP graft survival when administered with a minimal immunosuppressive drug regimen.
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Affiliation(s)
- M.B. Ezzelarab
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - D. Raich-Regue
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - L. Lu
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - A.F. Zahorchak
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - A. Perez-Gutierrez
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - A. Humar
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - M. Wijkstrom
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - M. Minervini
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - R.W. Wiseman
- Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI
| | - D.K.C. Cooper
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - A.E. Morelli
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - A.W. Thomson
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA,Corresponding author: Angus W. Thomson, PhD, DSc, University of Pittsburgh School of Medicine, 200 Lothrop Street, W1540 BST, Pittsburgh, PA 15261, Phone: (412) 624-6392,
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Cortvrindt C, Speeckaert R, Moerman A, Delanghe JR, Speeckaert MM. The role of interleukin-17A in the pathogenesis of kidney diseases. Pathology 2017; 49:247-258. [DOI: 10.1016/j.pathol.2017.01.003] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 12/26/2016] [Accepted: 01/19/2017] [Indexed: 01/13/2023]
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da Silva MB, da Cunha FF, Terra FF, Camara NOS. Old game, new players: Linking classical theories to new trends in transplant immunology. World J Transplant 2017; 7:1-25. [PMID: 28280691 PMCID: PMC5324024 DOI: 10.5500/wjt.v7.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/16/2016] [Accepted: 12/07/2016] [Indexed: 02/05/2023] Open
Abstract
The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.
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