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Zhao X, Zhang J, Li C, Kuang W, Deng J, Tan X, Li C, Li S. Mitochondrial mechanisms in Treg cell regulation: Implications for immunotherapy and disease treatment. Mitochondrion 2025; 80:101975. [PMID: 39491776 DOI: 10.1016/j.mito.2024.101975] [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: 06/11/2024] [Revised: 10/24/2024] [Accepted: 10/29/2024] [Indexed: 11/05/2024]
Abstract
Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis and preventing autoimmune diseases. Recent advances in immunometabolism have revealed the pivotal role of mitochondrial dynamics and metabolism in shaping Treg functionality. Tregs depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to support their suppressive functions and long-term survival. Mitochondrial processes such as fusion and fission significantly influence Treg activity, with mitochondrial fusion enhancing bioenergetic efficiency and reducing reactive oxygen species (ROS) production, thereby promoting Treg stability. In contrast, excessive mitochondrial fission disrupts ATP synthesis and elevates ROS levels, impairing Treg suppressive capacity. Furthermore, mitochondrial ROS act as critical signaling molecules in Treg regulation, where controlled levels stabilize FoxP3 expression, but excessive ROS leads to mitochondrial dysfunction and immune dysregulation. Mitophagy, as part of mitochondrial quality control, also plays an essential role in preserving Treg function. Understanding the intricate interplay between mitochondrial dynamics and Treg metabolism provides valuable insights for developing novel therapeutic strategies to treat autoimmune disorders and enhance immunotherapy in cancer.
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Affiliation(s)
- Xiaozhen Zhao
- Department of Rheumatology, National Centre for Children's Health Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Junmei Zhang
- Department of Rheumatology, National Centre for Children's Health Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Caifeng Li
- Department of Rheumatology, National Centre for Children's Health Beijing Children's Hospital, Capital Medical University, Beijing, China.
| | - Weiying Kuang
- Department of Rheumatology, National Centre for Children's Health Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Jianghong Deng
- Department of Rheumatology, National Centre for Children's Health Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Xiaohua Tan
- Department of Rheumatology, National Centre for Children's Health Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Chao Li
- Department of Rheumatology, National Centre for Children's Health Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Shipeng Li
- Department of Rheumatology, National Centre for Children's Health Beijing Children's Hospital, Capital Medical University, Beijing, China
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2
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Han JW, Park SH. Advancing immunosuppression in liver transplantation: the role of regulatory T cells in immune modulation and graft tolerance. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:257-272. [PMID: 39696994 PMCID: PMC11732766 DOI: 10.4285/ctr.24.0059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 11/23/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024]
Abstract
Prolonged immunosuppressive therapy in liver transplantation (LT) is associated with significant adverse effects, such as nephrotoxicity, metabolic complications, and heightened risk of infection or malignancy. Regulatory T cells (Tregs) represent a promising target for inducing immune tolerance in LT, with the potential to reduce or eliminate the need for life-long immunosuppression. This review summarizes current knowledge on the roles of Tregs in LT, highlighting their mechanisms and the impact of various immunosuppressive agents on Treg stability and function. The liver's distinct immunological microenvironment, characterized by tolerogenic antigen-presenting cells and high levels of interleukin (IL)-10 and transforming growth factor-β, positions this organ as an ideal setting for Treg-mediated tolerance. We discuss Treg dynamics in LT, their association with rejection risk, and their utility as biomarkers of transplant outcomes. Emerging strategies, including the use of low-dose calcineurin inhibitors with mammalian target of rapamycin inhibitors, adoptive Treg therapy, and low-dose IL-2, aim to enhance Treg function while providing sufficient immunosuppression. Thus, the future of LT involves precision medicine approaches that integrate Treg monitoring with tailored immunosuppressive protocols to optimize long-term outcomes for LT recipients.
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Affiliation(s)
- Ji Won Han
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
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3
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Alvarez-Salazar EK, Cortés-Hernández A, Arteaga-Cruz S, Soldevila G. Induced regulatory T cells as immunotherapy in allotransplantation and autoimmunity: challenges and opportunities. J Leukoc Biol 2024; 116:947-965. [PMID: 38630873 DOI: 10.1093/jleuko/qiae062] [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: 12/01/2023] [Revised: 02/14/2024] [Accepted: 02/21/2024] [Indexed: 04/19/2024] Open
Abstract
Regulatory T cells play a crucial role in the homeostasis of the immune response. Regulatory T cells are mainly generated in the thymus and are characterized by the expression of Foxp3, which is considered the regulatory T-cell master transcription factor. In addition, regulatory T cells can be induced from naive CD4+ T cells to express Foxp3 under specific conditions both in vivo (peripheral regulatory T cells) and in vitro (induced regulatory T cells). Both subsets of thymic regulatory T cells and peripheral regulatory T cells are necessary for the establishment of immune tolerance to self and non-self antigens. Although it has been postulated that induced regulatory T cells may be less stable compared to regulatory T cells, mainly due to epigenetic differences, accumulating evidence in animal models shows that induced regulatory T cells are stable in vivo and can be used for the treatment of inflammatory disorders, including autoimmune diseases and allogeneic transplant rejection. In this review, we describe the biological characteristics of induced regulatory T cells, as well as the key factors involved in induced regulatory T-cell transcriptional, metabolic, and epigenetic regulation, and discuss recent advances for de novo generation of stable regulatory T cells and their use as immunotherapeutic tools in different experimental models. Moreover, we discuss the challenges and considerations for the application of induced regulatory T cells in clinical trials and describe the new approaches proposed to achieve in vivo stability, including functional or metabolic reprogramming and epigenetic editing.
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Affiliation(s)
- Evelyn Katy Alvarez-Salazar
- Department of Immunology and National Laboratory of Flow Cytometry, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Circuito Escolar s/n, Ciudad Universitaria, Colonia Copilco, Delegación Coyoacan, Apartado Postal 70228, CP 04510 Mexico City, Mexico
| | - Arimelek Cortés-Hernández
- Department of Immunology and National Laboratory of Flow Cytometry, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Circuito Escolar s/n, Ciudad Universitaria, Colonia Copilco, Delegación Coyoacan, Apartado Postal 70228, CP 04510 Mexico City, Mexico
| | - Saúl Arteaga-Cruz
- Department of Immunology and National Laboratory of Flow Cytometry, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Circuito Escolar s/n, Ciudad Universitaria, Colonia Copilco, Delegación Coyoacan, Apartado Postal 70228, CP 04510 Mexico City, Mexico
| | - Gloria Soldevila
- Department of Immunology and National Laboratory of Flow Cytometry, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Circuito Escolar s/n, Ciudad Universitaria, Colonia Copilco, Delegación Coyoacan, Apartado Postal 70228, CP 04510 Mexico City, Mexico
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4
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Martin J, Hollowood Z, Chorlton J, Dyer C, Marelli-Berg F. Modulating regulatory T cell migration in the treatment of autoimmunity and autoinflammation. Curr Opin Pharmacol 2024; 77:102466. [PMID: 38906084 DOI: 10.1016/j.coph.2024.102466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/23/2024]
Abstract
Treatment of autoimmunity and autoinflammation with regulatory T cells has received much attention in the last twenty years. Despite the well-documented clinical benefit of Treg therapy, a large-scale application has proven elusive, mainly due to the extensive culture facilities required and associated costs. A possible way to overcome these hurdles in part is to target Treg migration to inflammatory sites using a small molecule. Here we review recent advances in this strategy and introduce the new concept of pharmacologically enhanced delivery of endogenous Tregs to control inflammation, which has been recently validated in humans.
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Affiliation(s)
- John Martin
- Division of Medicine, University College London, London, WC1E 6JF, UK; St George Street Capital, London, EC4R 1BE, UK.
| | | | | | - Carlene Dyer
- William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Federica Marelli-Berg
- William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
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Mashayekhi K, Khazaie K, Faubion WA, Kim GB. Biomaterial-enhanced treg cell immunotherapy: A promising approach for transplant medicine and autoimmune disease treatment. Bioact Mater 2024; 37:269-298. [PMID: 38694761 PMCID: PMC11061617 DOI: 10.1016/j.bioactmat.2024.03.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/20/2024] [Accepted: 03/25/2024] [Indexed: 05/04/2024] Open
Abstract
Regulatory T cells (Tregs) are crucial for preserving tolerance in the body, rendering Treg immunotherapy a promising treatment option for both organ transplants and autoimmune diseases. Presently, organ transplant recipients must undergo lifelong immunosuppression to prevent allograft rejection, while autoimmune disorders lack definitive cures. In the last years, there has been notable advancement in comprehending the biology of both antigen-specific and polyclonal Tregs. Clinical trials involving Tregs have demonstrated their safety and effectiveness. To maximize the efficacy of Treg immunotherapy, it is essential for these cells to migrate to specific target tissues, maintain stability within local organs, bolster their suppressive capabilities, and ensure their intended function's longevity. In pursuit of these goals, the utilization of biomaterials emerges as an attractive supportive strategy for Treg immunotherapy in addressing these challenges. As a result, the prospect of employing biomaterial-enhanced Treg immunotherapy holds tremendous promise as a treatment option for organ transplant recipients and individuals grappling with autoimmune diseases in the near future. This paper introduces strategies based on biomaterial-assisted Treg immunotherapy to enhance transplant medicine and autoimmune treatments.
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Affiliation(s)
- Kazem Mashayekhi
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | | | - William A. Faubion
- Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Gloria B. Kim
- Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Scottsdale, AZ, USA
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6
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Knoedler L, Dean J, Diatta F, Thompson N, Knoedler S, Rhys R, Sherwani K, Ettl T, Mayer S, Falkner F, Kilian K, Panayi AC, Iske J, Safi AF, Tullius SG, Haykal S, Pomahac B, Kauke-Navarro M. Immune modulation in transplant medicine: a comprehensive review of cell therapy applications and future directions. Front Immunol 2024; 15:1372862. [PMID: 38650942 PMCID: PMC11033354 DOI: 10.3389/fimmu.2024.1372862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 03/22/2024] [Indexed: 04/25/2024] Open
Abstract
Balancing the immune response after solid organ transplantation (SOT) and vascularized composite allotransplantation (VCA) remains an ongoing clinical challenge. While immunosuppressants can effectively reduce acute rejection rates following transplant surgery, some patients still experience recurrent acute rejection episodes, which in turn may progress to chronic rejection. Furthermore, these immunosuppressive regimens are associated with an increased risk of malignancies and metabolic disorders. Despite significant advancements in the field, these IS related side effects persist as clinical hurdles, emphasizing the need for innovative therapeutic strategies to improve transplant survival and longevity. Cellular therapy, a novel therapeutic approach, has emerged as a potential pathway to promote immune tolerance while minimizing systemic side-effects of standard IS regiments. Various cell types, including chimeric antigen receptor T cells (CAR-T), mesenchymal stromal cells (MSCs), regulatory myeloid cells (RMCs) and regulatory T cells (Tregs), offer unique immunomodulatory properties that may help achieve improved outcomes in transplant patients. This review aims to elucidate the role of cellular therapies, particularly MSCs, T cells, Tregs, RMCs, macrophages, and dendritic cells in SOT and VCA. We explore the immunological features of each cell type, their capacity for immune regulation, and the prospective advantages and obstacles linked to their application in transplant patients. An in-depth outline of the current state of the technology may help SOT and VCA providers refine their perioperative treatment strategies while laying the foundation for further trials that investigate cellular therapeutics in transplantation surgery.
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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
| | - Jillian Dean
- School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Fortunay Diatta
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Noelle Thompson
- University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
| | - Samuel Knoedler
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Richmond Rhys
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Khalil Sherwani
- Department of Hand, Plastic and Reconstructive Surgery, Burn Center, Berufsgenossenschaft (BG) Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
| | - Tobias Ettl
- Department of Dental, Oral and Maxillofacial Surgery, Regensburg, Germany
| | - Simon Mayer
- University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
| | - Florian Falkner
- Department of Hand, Plastic and Reconstructive Surgery, Burn Center, Berufsgenossenschaft (BG) Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
| | - Katja Kilian
- Department of Hand, Plastic and Reconstructive Surgery, Burn Center, Berufsgenossenschaft (BG) Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
| | - Adriana C. Panayi
- Department of Hand, Plastic and Reconstructive Surgery, Burn Center, Berufsgenossenschaft (BG) Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
| | - Jasper Iske
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Ali-Farid Safi
- Faculty of Medicine, University of Bern, Bern, Switzerland
- Craniologicum, Center for Cranio-Maxillo-Facial Surgery, Bern, Switzerland
| | - Stefan G. Tullius
- Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Siba Haykal
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Bohdan Pomahac
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Martin Kauke-Navarro
- Department of Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
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Efe O, Gassen RB, Morena L, Ganchiku Y, Al Jurdi A, Lape IT, Ventura-Aguiar P, LeGuern C, Madsen JC, Shriver Z, Babcock GJ, Borges TJ, Riella LV. A humanized IL-2 mutein expands Tregs and prolongs transplant survival in preclinical models. J Clin Invest 2024; 134:e173107. [PMID: 38426492 PMCID: PMC10904054 DOI: 10.1172/jci173107] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 01/05/2024] [Indexed: 03/02/2024] Open
Abstract
Long-term organ transplant survival remains suboptimal, and life-long immunosuppression predisposes transplant recipients to an increased risk of infection, malignancy, and kidney toxicity. Promoting the regulatory arm of the immune system by expanding Tregs may allow immunosuppression minimization and improve long-term graft outcomes. While low-dose IL-2 treatment can expand Tregs, it has a short half-life and off-target expansion of NK and effector T cells, limiting its clinical applicability. Here, we designed a humanized mutein IL-2 with high Treg selectivity and a prolonged half-life due to the fusion of an Fc domain, which we termed mIL-2. We showed selective and sustainable Treg expansion by mIL-2 in 2 murine models of skin transplantation. This expansion led to donor-specific tolerance through robust increases in polyclonal and antigen-specific Tregs, along with enhanced Treg-suppressive function. We also showed that Treg expansion by mIL-2 could overcome the failure of calcineurin inhibitors or costimulation blockade to prolong the survival of major-mismatched skin grafts. Validating its translational potential, mIL-2 induced a selective and sustainable in vivo Treg expansion in cynomolgus monkeys and showed selectivity for human Tregs in vitro and in a humanized mouse model. This work demonstrated that mIL-2 can enhance immune regulation and promote long-term allograft survival, potentially minimizing immunosuppression.
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Affiliation(s)
- Orhan Efe
- Center for Transplantation Sciences, Department of Surgery
- Division of Nephrology, Department of Medicine, and
| | | | - Leela Morena
- Center for Transplantation Sciences, Department of Surgery
| | | | - Ayman Al Jurdi
- Center for Transplantation Sciences, Department of Surgery
- Division of Nephrology, Department of Medicine, and
| | | | | | | | - Joren C. Madsen
- Center for Transplantation Sciences, Department of Surgery
- Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | | | - Leonardo V. Riella
- Center for Transplantation Sciences, Department of Surgery
- Division of Nephrology, Department of Medicine, and
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Xiong Y, Wang Y, Wu M, Chen S, Lei H, Mu H, Yu H, Hou Y, Tang K, Chen X, Dong J, Wang X, Chen L. Aberrant NK cell profile in gestational diabetes mellitus with fetal growth restriction. Front Immunol 2024; 15:1346231. [PMID: 38375483 PMCID: PMC10875967 DOI: 10.3389/fimmu.2024.1346231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 01/17/2024] [Indexed: 02/21/2024] Open
Abstract
Gestational diabetes mellitus (GDM) is a gestational disorder characterized by hyperglycemia, that can lead to dysfunction of diverse cells in the body, especially the immune cells. It has been reported that immune cells, specifically natural killer (NK) cells, play a crucial role in normal pregnancy. However, it remains unknown how hyperglycemia affects NK cell dysfunction thus participates in the development of GDM. In this experiment, GDM mice were induced by an intraperitoneal injection of streptozotocin (STZ) after pregnancy and it has been found that the intrauterine growth restriction occurred in mice with STZ-induced GDM, accompanied by the changed proportion and function of NK cells. The percentage of cytotoxic CD27-CD11b+ NK cells was significantly increased, while the proportion of nourished CD27-CD11b- NK cells was significantly reduced in the decidua of GDM mice. Likewise, the same trend appeared in the peripheral blood NK cell subsets of GDM patients. What's more, after intrauterine reinfusion of NK cells to GDM mice, the fetal growth restriction was alleviated and the proportion of NK cells was restored. Our findings provide a theoretical and experimental basis for further exploring the pathogenesis of GDM.
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Affiliation(s)
- Yujing Xiong
- Department of Immunology, Air Force Medical University, Xi’an, Shaanxi, China
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Yazhen Wang
- Department of Immunology, Air Force Medical University, Xi’an, Shaanxi, China
| | - Mengqi Wu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Shuqiang Chen
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Hui Lei
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Hui Mu
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Haikun Yu
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Yongli Hou
- Department of Immunology, Air Force Medical University, Xi’an, Shaanxi, China
| | - Kang Tang
- Department of Immunology, Air Force Medical University, Xi’an, Shaanxi, China
| | - Xutao Chen
- Department of Immunology, Air Force Medical University, Xi’an, Shaanxi, China
| | - Jie Dong
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Xiaohong Wang
- Reproductive Medical Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Lihua Chen
- Department of Immunology, Air Force Medical University, Xi’an, Shaanxi, China
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Møller DL, Sørensen SS, Perch M, Gustafsson F, Hald A, Knudsen AD, Abdulovski R, Arentoft NS, Lundgren J, Rasmussen A, Ostrowski SR, Nielsen SD. Differences in toll-like receptor ligand-induced cytokine concentrations before and after solid organ transplantation: A prospective, observational cohort study in a clinical setting. Scand J Immunol 2024; 99:e13337. [PMID: 38168873 DOI: 10.1111/sji.13337] [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: 07/17/2023] [Revised: 10/09/2023] [Accepted: 10/20/2023] [Indexed: 01/05/2024]
Abstract
Reliable methods to assess immune function after solid organ transplantation (SOT) are needed to guide dosing of immunosuppression. We hypothesized that toll-like receptor ligand-induced cytokine concentrations would decrease post-transplantation due to the use of immunosuppressive medication. Furthermore, we hypothesized that induced cytokine concentrations pre-transplantation would be higher in recipients with episodes of acute rejection post-transplantation due to underlying immunological dispositions. We aimed to investigate toll-like receptor ligand-induced cytokine concentrations by TruCulture©, a standardized immunoassay, in SOT recipients before and 3 months after SOT and explored associations with methylprednisolone-treated acute rejections. We conducted a prospective, observational cohort study including 123 participants (67 liver, 32 kidney and 24 lung transplant recipients). Whole blood was stimulated for 22 h with: (A) Lipopolysaccharide (LPS), (B) Resiquimod, (C) Polyinosinic:polycytidylic acid (Poly I:C) and (D) a blank control. Cytokine concentrations (TNF-α, IL-1β, IL-6, IL-8, IL-10, IL-12p40, IL-17A, IFN-α and IFN-γ) were measured by Luminex. 30 participants developed methylprednisolone-treated acute rejection at a median of 9 days (IQR 5-17) post-SOT. We found that all induced cytokine concentrations decreased post-SOT except from LPS-induced and Poly I:C-induced IL-10. The induced cytokine concentration pre-transplantation did not differ in recipients with or without acute rejection. In conclusion, the induced cytokine concentrations decreased for all stimuli post-SOT, except the anti-inflammatory cytokine IL-10. Importantly, recipients developing early acute rejection did not differ in induced cytokine concentrations pre-SOT. Thus, the use of a standardized assay in SOT is feasible in a clinical setting and may provide important information on the immune function post-SOT.
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Affiliation(s)
- Dina Leth Møller
- Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Søren Schwartz Sørensen
- Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Michael Perch
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Cardiology, Section for Lung Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Finn Gustafsson
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Annemette Hald
- Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Andreas Delhbaek Knudsen
- Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ranya Abdulovski
- Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Nicoline Stender Arentoft
- Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jens Lundgren
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Centre of Excellence for Health, Immunity, and Infections, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Allan Rasmussen
- Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Sisse Rye Ostrowski
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Susanne Dam Nielsen
- Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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10
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Liu Z, Baines KJ, Niessen NM, Heer MK, Clark D, Bishop GA, Trevillian PR. Characterizing Foxp3 + and Foxp3 - T cells in the homeostatic state and after allo-activation: resting CD4 +Foxp3 + Tregs have molecular characteristics of activated T cells. Front Immunol 2024; 15:1292158. [PMID: 38333213 PMCID: PMC10850883 DOI: 10.3389/fimmu.2024.1292158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/08/2024] [Indexed: 02/10/2024] Open
Abstract
Due to the intracellular expression of Foxp3 it is impossible to purify viable Foxp3+ cells on the basis of Foxp3 staining. Consequently CD4+Foxp3+ regulatory T cells (Tregs) in mice have mostly been characterized using CD4+CD25+ T cells or GFP-Foxp3 reporter T cells. However, these two populations cannot faithfully represent Tregs as the expression of CD25 and Foxp3 does not completely overlap and GFP+Foxp3+ reporter T cells have been reported to be functionally altered. The aim of this study was to characterize normal Tregs without separating Foxp3+ and Foxp3- cells for the expression of the main functional molecules and proliferation behaviors by flow cytometry and to examine their gene expression characteristics through differential gene expression. Our data showed that the expressions of Foxp3, CD25, CTLA-4 (both intracellular and cell surface) and PD-1 was mostly confined to CD4+ T cells and the expression of Foxp3 did not completely overlap with the expression of CD25, CTLA-4 or PD-1. Despite higher levels of expression of the T cell inhibitory molecules CTLA-4 and PD-1, Tregs maintained higher levels of Ki-67 expression in the homeostatic state and had greater proliferation in vivo after allo-activation than Tconv. Differential gene expression analysis revealed that resting Tregs exhibited immune activation markers characteristic of activated Tconv. This is consistent with the flow data that the T cell activation markers CD25, CTLA-4, PD-1, and Ki-67 were much more strongly expressed by Tregs than Tconv in the homeostatic state.
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Affiliation(s)
- Zilei Liu
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
- School of Medicine and Public Health, College of Medicine, Health and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
| | - Katherine J. Baines
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
- School of Biomedical Sciences and Pharmacy, College of Medicine, Health and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
| | - Natalie M. Niessen
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
| | - Munish K. Heer
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
| | - David Clark
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
- School of Medicine and Public Health, College of Medicine, Health and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
| | - G. Alexander Bishop
- Transplantation Immunobiology Group, University of Sydney Central Clinical School, Charles Perkins Centre, Faculty of Medicine and Health, Sydney, NSW, Australia
| | - Paul R. Trevillian
- Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
- Transplant and Surgical Immunology Theme, Immune Health Research Program, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia
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11
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James EA, Joglekar AV, Linnemann AK, Russ HA, Kent SC. The beta cell-immune cell interface in type 1 diabetes (T1D). Mol Metab 2023; 78:101809. [PMID: 37734713 PMCID: PMC10622886 DOI: 10.1016/j.molmet.2023.101809] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 09/01/2023] [Accepted: 09/15/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND T1D is an autoimmune disease in which pancreatic islets of Langerhans are infiltrated by immune cells resulting in the specific destruction of insulin-producing islet beta cells. Our understanding of the factors leading to islet infiltration and the interplay of the immune cells with target beta cells is incomplete, especially in human disease. While murine models of T1D have provided crucial information for both beta cell and autoimmune cell function, the translation of successful therapies in the murine model to human disease has been a challenge. SCOPE OF REVIEW Here, we discuss current state of the art and consider knowledge gaps concerning the interface of the islet beta cell with immune infiltrates, with a focus on T cells. We discuss pancreatic and immune cell phenotypes and their impact on cell function in health and disease, which we deem important to investigate further to attain a more comprehensive understanding of human T1D disease etiology. MAJOR CONCLUSIONS The last years have seen accelerated development of approaches that allow comprehensive study of human T1D. Critically, recent studies have contributed to our revised understanding that the pancreatic beta cell assumes an active role, rather than a passive position, during autoimmune disease progression. The T cell-beta cell interface is a critical axis that dictates beta cell fate and shapes autoimmune responses. This includes the state of the beta cell after processing internal and external cues (e.g., stress, inflammation, genetic risk) that that contributes to the breaking of tolerance by hyperexpression of human leukocyte antigen (HLA) class I with presentation of native and neoepitopes and secretion of chemotactic factors to attract immune cells. We anticipate that emerging insights about the molecular and cellular aspects of disease initiation and progression processes will catalyze the development of novel and innovative intervention points to provide additional therapies to individuals affected by T1D.
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Affiliation(s)
- Eddie A James
- Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Alok V Joglekar
- Center for Systems Immunology and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Amelia K Linnemann
- Center for Diabetes and Metabolic Diseases, and Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Holger A Russ
- Diabetes Institute, University of Florida, Gainesville, FL, USA; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
| | - Sally C Kent
- Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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12
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Aljabban J, Burlingham W, Lucey MR. The potential role of infusions of T regulatory cells in inducing and maintaining liver allograft tolerance. Clin Liver Dis (Hoboken) 2023; 22:146-151. [PMID: 37908871 PMCID: PMC10615501 DOI: 10.1097/cld.0000000000000038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/18/2022] [Indexed: 11/02/2023] Open
Abstract
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Affiliation(s)
- Jihad Aljabban
- Department of Medicine, The University of Wisconsin Hospital and Clinics
| | | | - Michael R. Lucey
- Department of Medicine, The University of Wisconsin Hospital and Clinics
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13
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Nahm DH. Regulatory T Cell-Targeted Immunomodulatory Therapy for Long-Term Clinical Improvement of Atopic Dermatitis: Hypotheses and Perspectives. Life (Basel) 2023; 13:1674. [PMID: 37629531 PMCID: PMC10455293 DOI: 10.3390/life13081674] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/28/2023] [Accepted: 07/30/2023] [Indexed: 08/27/2023] Open
Abstract
Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disorder characterized by itching and eczematous lesions. It is often associated with a personal or familial history of allergic diseases. Allergic inflammation induced by immunoglobulin E and T-helper type 2 (Th2) cell responses to common environmental agents has been suggested to play an essential role in AD pathogenesis. The standard therapies for AD, including topical or systemic agents, focus on controlling skin inflammation. Recently developed monoclonal antibody to interleukin-4 receptor alpha or Janus kinase inhibitors can provide significant clinical improvements in patients with AD by inhibiting Th2 cell-mediated skin inflammation. However, the clinical efficacy of the Th2 cell-targeted therapy is transient and incomplete in patients with AD. Patients with AD are seeking a permanent cure. Therefore, the development of novel immunomodulatory strategies that can improve a long-term clinical outcome and provide a long-term treatment-free clinical remission of AD (disease-modifying therapy) is needed. Regulatory T (Treg) cells play a critical role in the maintenance of immune tolerance and suppress the development of autoimmune and allergic diseases. This review provides three working hypotheses and perspectives for the treatment of AD by Treg cell activation. (1) A decreased number or function of Treg cells is a critical event that causes the activation of Th2 cells, leading to the development and maintenance of AD. (2) Activation of Treg cells is an effective therapeutic approach for AD. (3) Many different immunomodulatory strategies activating Treg cells can provide a long-term clinical improvement of AD by induction of immune tolerance. The Treg cell-targeted immunomodulatory therapies for AD include allergen immunotherapy, microbiota, vitamin D, polyvalent human immunoglobulin G, monoclonal antibodies to the surface antigens of T cell or antigen-presenting cell, and adoptive transfer of autologous Treg cells or genetically engineered Treg cells expanded in vitro.
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Affiliation(s)
- Dong-Ho Nahm
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
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14
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Abhishek K, Nidhi M, Chandran S, Shevkoplyas SS, Mohan C. Manufacturing regulatory T cells for adoptive cell therapy in immune diseases: A critical appraisal. Clin Immunol 2023; 251:109328. [PMID: 37086957 PMCID: PMC11003444 DOI: 10.1016/j.clim.2023.109328] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/04/2023] [Accepted: 04/07/2023] [Indexed: 04/24/2023]
Abstract
Regulatory T cells (Tregs) are a unique subset of lymphocytes that play a vital role in regulating the immune system by suppressing unwanted immune responses and thus preventing autoimmune diseases and inappropriate inflammatory reactions. In preclinical and clinical trials, these cells have demonstrated the ability to prevent and treat graft vs. host disease, alleviate autoimmune symptoms, and promote transplant tolerance. In this review, we provide a background on Treg cells with a focus on important Treg cell markers and Treg subsets, and outline the methodology currently used for manufacturing adoptive regulatory T cell therapies (TRACT). Finally, we discuss the approaches and outcomes of several clinical trials in which Tregs have been adoptively transferred to patients.
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Affiliation(s)
- Kumar Abhishek
- Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, United States of America
| | - Malavika Nidhi
- Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, United States of America
| | - Srinandhini Chandran
- Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, United States of America
| | - Sergey S Shevkoplyas
- Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, United States of America.
| | - Chandra Mohan
- Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, United States of America.
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15
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Wang B, Zhang Z, Liu W, Tan B. Targeting regulatory T cells in gastric cancer: Pathogenesis, immunotherapy, and prognosis. Biomed Pharmacother 2023; 158:114180. [PMID: 36586241 DOI: 10.1016/j.biopha.2022.114180] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/16/2022] [Accepted: 12/28/2022] [Indexed: 12/31/2022] Open
Abstract
Gastric cancer (GC) remains one of the most common malignancies worldwide. Despite immune-checkpoint inhibitors (ICIs) has revolutionized cancer treatment and obtained durable clinical responses, only a fraction of GC patients benefit from it. As an important component of T cells, regulatory T cells (Tregs) play a vital role in the pathogenesis of GC, keep a core balance between immune suppression and autoimmunity, and function as predictive biomarkers for prognosis of GC patients. In this review, we discuss the role of Tregs in the pathogenesis of GC, and targeting Tregs via influencing their transcription factor, migration, co-stimulatory receptors, immune checkpoints, and cytokines. We also focus on the currently important findings of Tregs metabolism including amino acid, fatty acid, and lactic acid metabolism of GC. The emerging role of microbiome and clinical combined therapy in modulating Tregs in GC treatment is also summarized. Meanwhile, this review recapitulates a novel regulator, magnesium, is involved in mediating Tregs in GC. These research advances on Treg-related strategies provide new insights and challenges for GC progression, treatment, and prognosis. And we hope our review can stimulate further discovery and implication of mediators and pathways targeting Tregs.
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Affiliation(s)
- Bingyu Wang
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, 050011 Shijiazhuang, China
| | - Zaibo Zhang
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, 050011 Shijiazhuang, China
| | - Wenbo Liu
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, 050011 Shijiazhuang, China
| | - Bibo Tan
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, 050011 Shijiazhuang, China.
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16
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Hennessy C, Deptula M, Hester J, Issa F. Barriers to Treg therapy in Europe: From production to regulation. Front Med (Lausanne) 2023; 10:1090721. [PMID: 36744143 PMCID: PMC9892909 DOI: 10.3389/fmed.2023.1090721] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 01/03/2023] [Indexed: 01/20/2023] Open
Abstract
There has been an increased interest in cell based therapies for a range of medical conditions in the last decade. This explosion in novel therapeutics research has led to the development of legislation specifically focused on cell and gene based therapies. In Europe, the European medicines agency (EMA) designates any medicines for human use which are based on genes, tissues, or cells as advanced therapy medicinal products or advanced therapy medicinal products (ATMPs). In this article we discuss the hurdles to widespread adoption of ATMPs in Europe, with a focus on regulatory T cells (Tregs). There are numerous barriers which must be overcome before mainstream adoption of Treg therapy becomes a reality. The source of the cells, whether to use autologous or allogenic cells, and the methods through which they are isolated and expanded, must all meet strict good manufacturing practice (GMP) standards to allow use of the products in humans. GMP compliance is costly, with the equipment and reagents providing a significant cost barrier and requiring specialized facilities and personnel. Conforming to the regulations set centrally by the EMA is difficult, and the different interpretations of the regulations across the various member states further complicates the regulatory approval process. The end products then require a complex and robust distribution network to ensure timely delivery of potentially life saving treatments to patients. In a European market whose logistics networks have been hammered by COVID and Brexit, ensuring rapid and reliable delivery systems is a more complex task than ever. In this article we will examine the impact of these barriers on the development and adoption of Tregs in Europe, and potential approaches which could facilitate more widespread use of Tregs, instead of its current concentration in a few very specialized centers.
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Affiliation(s)
- Conor Hennessy
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Milena Deptula
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
- Laboratory of Tissue Engineering and Regenerative Medicine, Division of Embryology, Medical University of Gdańsk, Gdańsk, Poland
| | - Joanna Hester
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Fadi Issa
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
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17
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Oparaugo NC, Ouyang K, Nguyen NPN, Nelson AM, Agak GW. Human Regulatory T Cells: Understanding the Role of Tregs in Select Autoimmune Skin Diseases and Post-Transplant Nonmelanoma Skin Cancers. Int J Mol Sci 2023; 24:1527. [PMID: 36675037 PMCID: PMC9864298 DOI: 10.3390/ijms24021527] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/04/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis by modulating how the immune system is activated. Several studies have documented the critical role of Tregs in suppressing the functions of effector T cells and antigen-presenting cells. Under certain conditions, Tregs can lose their suppressive capability, leading to a compromised immune system. For example, mutations in the Treg transcription factor, Forkhead box P3 (FOXP3), can drive the development of autoimmune diseases in multiple organs within the body. Furthermore, mutations leading to a reduction in the numbers of Tregs or a change in their function facilitate autoimmunity, whereas an overabundance can inhibit anti-tumor and anti-pathogen immunity. This review discusses the characteristics of Tregs and their mechanism of action in select autoimmune skin diseases, transplantation, and skin cancer. We also examine the potential of Tregs-based cellular therapies in autoimmunity.
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Affiliation(s)
- Nicole Chizara Oparaugo
- David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Kelsey Ouyang
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
| | | | - Amanda M. Nelson
- Department of Dermatology, Penn State University College of Medicine, Hershey, PA 17033, USA
| | - George W. Agak
- Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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18
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Cheung J, Zahorowska B, Suranyi M, Wong JKW, Diep J, Spicer ST, Verma ND, Hodgkinson SJ, Hall BM. CD4 +CD25 + T regulatory cells in renal transplantation. Front Immunol 2022; 13:1017683. [PMID: 36426347 PMCID: PMC9681496 DOI: 10.3389/fimmu.2022.1017683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 10/13/2022] [Indexed: 09/14/2023] Open
Abstract
The immune response to an allograft activates lymphocytes with the capacity to cause rejection. Activation of CD4+CD25+Foxp3+T regulatory cells (Treg) can down-regulate allograft rejection and can induce immune tolerance to the allograft. Treg represent <10% of peripheral CD4+T cells and do not markedly increase in tolerant hosts. CD4+CD25+Foxp3+T cells include both resting and activated Treg that can be distinguished by several markers, many of which are also expressed by effector T cells. More detailed characterization of Treg to identify increased activated antigen-specific Treg may allow reduction of non-specific immunosuppression. Natural thymus derived resting Treg (tTreg) are CD4+CD25+Foxp3+T cells and only partially inhibit alloantigen presenting cell activation of effector cells. Cytokines produced by activated effector cells activate these tTreg to more potent alloantigen-activated Treg that may promote a state of operational tolerance. Activated Treg can be distinguished by several molecules they are induced to express, or whose expression they have suppressed. These include CD45RA/RO, cytokine receptors, chemokine receptors that alter pathways of migration and transcription factors, cytokines and suppression mediating molecules. As the total Treg population does not increase in operational tolerance, it is the activated Treg which may be the most informative to monitor. Here we review the methods used to monitor peripheral Treg, the effect of immunosuppressive regimens on Treg, and correlations with clinical outcomes such as graft survival and rejection. Experimental therapies involving ex vivo Treg expansion and administration in renal transplantation are not reviewed.
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Affiliation(s)
- Jason Cheung
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
| | | | - Michael Suranyi
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
| | | | - Jason Diep
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Stephen T. Spicer
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Nirupama D. Verma
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
- Immune Tolerance Laboratory, Ingham Institute for Applied Medical Research, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Suzanne J. Hodgkinson
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
- Immune Tolerance Laboratory, Ingham Institute for Applied Medical Research, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Bruce M. Hall
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
- Immune Tolerance Laboratory, Ingham Institute for Applied Medical Research, University of New South Wales (UNSW), Sydney, NSW, Australia
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19
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Tang Q, Leung J, Peng Y, Sanchez-Fueyo A, Lozano JJ, Lam A, Lee K, Greenland JR, Hellerstein M, Fitch M, Li KW, Esensten JH, Putnam AL, Lares A, Nguyen V, Liu W, Bridges ND, Odim J, Demetris AJ, Levitsky J, Taner T, Feng S. Selective decrease of donor-reactive T regs after liver transplantation limits T reg therapy for promoting allograft tolerance in humans. Sci Transl Med 2022; 14:eabo2628. [PMID: 36322627 PMCID: PMC11016119 DOI: 10.1126/scitranslmed.abo2628] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2024]
Abstract
Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (Tregs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen-reactive Treg (darTreg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darTreg infusion, 5 received darTregs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 106 cells. darTreg infusion was not associated with adverse events. Two darTreg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darTregs. Mechanistic studies revealed generalized Treg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of Treg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.
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Affiliation(s)
- Qizhi Tang
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
| | - Joey Leung
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Yani Peng
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King’s College London University, London WC2R 2LS, UK
| | - Juan-Jose Lozano
- Bioinformatic Platform, Biomedical Research Center in Hepatic and Digestive Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Alice Lam
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Karim Lee
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - John R. Greenland
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Medical Service, San Francisco VA Health Care System, San Francisco, CA 94121, USA
| | - Marc Hellerstein
- Nutrition Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Mark Fitch
- Nutrition Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Kelvin W. Li
- Nutrition Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Jonathan H. Esensten
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
- Department of Lab Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Amy L. Putnam
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Angela Lares
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Vinh Nguyen
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Weihong Liu
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Nancy D. Bridges
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA
| | - Jonah Odim
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA
| | - Anthony J. Demetris
- Thomas E. Starzl Transplantation Institute and Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Josh Levitsky
- Department of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Timucin Taner
- Departments of Surgery and Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Sandy Feng
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
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20
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Anderson RL, DiMeglio LA, Mander AP, Dayan CM, Linsley PS, Herold KC, Marinac M, Ahmed ST. Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes. Diabetes Care 2022; 45:2189-2201. [PMID: 36150059 PMCID: PMC9911317 DOI: 10.2337/dc22-0308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 07/19/2022] [Indexed: 02/06/2023]
Abstract
It has been 100 years since the life-saving discovery of insulin, yet daily management of type 1 diabetes (T1D) remains challenging. Even with closed-loop systems, the prevailing need for persons with T1D to attempt to match the kinetics of insulin activity with the kinetics of carbohydrate metabolism, alongside dynamic life factors affecting insulin requirements, results in the need for frequent interventions to adjust insulin dosages or consume carbohydrates to correct mismatches. Moreover, peripheral insulin dosing leaves the liver underinsulinized and hyperglucagonemic and peripheral tissues overinsulinized relative to their normal physiologic roles in glucose homeostasis. Disease-modifying therapies (DMT) to preserve and/or restore functional β-cell mass with controlled or corrected autoimmunity would simplify exogenous insulin need, thereby reducing disease mortality, morbidity, and management burdens. However, identifying effective DMTs for T1D has proven complex. There is some consensus that combination DMTs are needed for more meaningful clinical benefit. Other complexities are addressable with more innovative trial designs and logistics. While no DMT has yet been approved for marketing, existing regulatory guidance provides opportunities to further "de-risk" development. The T1D development ecosystem can accelerate progress by using more innovative ways for testing DMTs for T1D. This perspective outlines suggestions for accelerating evaluation of candidate T1D DMTs, including combination therapies, by use of innovative trial designs, enhanced logistical coordination of efforts, and regulatory guidance for expedited development, combination therapies, and adaptive designs.
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Affiliation(s)
| | - Linda A. DiMeglio
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
| | - Adrian P. Mander
- Centre for Trials Research, Cardiff University School of Medicine, Cardiff, U.K
| | - Colin M. Dayan
- Centre for Endocrine and Diabetes Science, Cardiff University School of Medicine, Cardiff, U.K
| | - Peter S. Linsley
- Systems Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA
| | - Kevan C. Herold
- Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT
| | | | - Simi T. Ahmed
- New York Stem Cell Foundation Research Institute, New York, NY
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21
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Lentz LS, Stutz AJ, Meyer N, Schubert K, Karkossa I, von Bergen M, Zenclussen AC, Schumacher A. Human chorionic gonadotropin promotes murine Treg cells and restricts pregnancy-harmful proinflammatory Th17 responses. Front Immunol 2022; 13:989247. [PMID: 36203576 PMCID: PMC9531259 DOI: 10.3389/fimmu.2022.989247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 08/25/2022] [Indexed: 11/15/2022] Open
Abstract
An equilibrium between proinflammatory and anti-inflammatory immune responses is essential for maternal tolerance of the fetus throughout gestation. To study the participation of fetal tissue-derived factors in this delicate immune balance, we analyzed the effects of human chorionic gonadotropin (hCG) on murine Treg cells and Th17 cells in vitro, and on pregnancy outcomes, fetal and placental growth, blood flow velocities and remodeling of the uterine vascular bed in vivo. Compared with untreated CD4+CD25+ T cells, hCG increased the frequency of Treg cells upon activation of the LH/CG receptor. hCG, with the involvement of IL-2, also interfered with induced differentiation of CD4+ T cells into proinflammatory Th17 cells. In already differentiated Th17 cells, hCG induced an anti-inflammatory profile. Transfer of proinflammatory Th17 cells into healthy pregnant mice promoted fetal rejection, impaired fetal growth and resulted in insufficient remodeling of uterine spiral arteries, and abnormal flow velocities. Our works show that proinflammatory Th17 cells have a negative influence on pregnancy that can be partly avoided by in vitro re-programming of proinflammatory Th17 cells with hCG.
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Affiliation(s)
- Lea S. Lentz
- Experimental Obstetrics and Gynecology, Medical Faculty, Health Campus Immunology, Infectilogy and Inflammation (GC-I), Otto-von-Guericke University, Magdeburg, Germany
| | - Annika J. Stutz
- Experimental Obstetrics and Gynecology, Medical Faculty, Health Campus Immunology, Infectilogy and Inflammation (GC-I), Otto-von-Guericke University, Magdeburg, Germany
| | - Nicole Meyer
- Experimental Obstetrics and Gynecology, Medical Faculty, Health Campus Immunology, Infectilogy and Inflammation (GC-I), Otto-von-Guericke University, Magdeburg, Germany
- Department of Environmental Immunology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Kristin Schubert
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Isabel Karkossa
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
- Faculty of Life Sciences, Institute of Biochemistry, University of Leipzig, Leipzig, Germany
- German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany
| | - Ana C. Zenclussen
- Experimental Obstetrics and Gynecology, Medical Faculty, Health Campus Immunology, Infectilogy and Inflammation (GC-I), Otto-von-Guericke University, Magdeburg, Germany
- Department of Environmental Immunology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Anne Schumacher
- Experimental Obstetrics and Gynecology, Medical Faculty, Health Campus Immunology, Infectilogy and Inflammation (GC-I), Otto-von-Guericke University, Magdeburg, Germany
- Department of Environmental Immunology, Helmholtz Centre for Environmental Research, Leipzig, Germany
- *Correspondence: Anne Schumacher,
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22
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Kang IH, Baliga UK, Chatterjee S, Chakraborty P, Choi S, Buchweitz N, Li H, Wu Y, Yao H, Mehrotra S, Mehrotra M. Quantitative increase in T regulatory cells enhances bone remodeling in osteogenesis imperfecta. iScience 2022; 25:104818. [PMID: 36034228 PMCID: PMC9400089 DOI: 10.1016/j.isci.2022.104818] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 06/07/2022] [Accepted: 07/19/2022] [Indexed: 02/03/2023] Open
Abstract
Osteogenesis imperfecta (OI) is characterized by repeated bone fractures. Recent studies have shown that T lymphocytes and regulatory T cells (Tregs) regulate the functions of osteoclasts and osteoblasts, thus playing a role in bone turnover. We demonstrate an activated effector phenotype and higher secretion of pro-inflammatory cytokines, IFN-γ, and TNF-α in OI peripheral T cells as compared with wild-type (WT). Suppressive Tregs (spleen and thymus) were qualitatively similar, whereas there was a quantitative decrease in OI versus WT. Restoring Treg numbers by systemic transplantation in OI mice resulted in reduced T cell activation and effector cytokine secretion that correlated with significant improvements in tibial trabecular and cortical bone parameters and stiffness of femur, along with increased osteoblast mineralization and decreased osteoclast numbers. Therefore, Tregs can dampen the pro-inflammatory environment and enhance bone remodeling in OI mice. Thus, this study will be helpful in developing future autologous immunotherapy-based treatment modalities for OI.
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Affiliation(s)
- In-Hong Kang
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Uday K. Baliga
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Shilpak Chatterjee
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Paramita Chakraborty
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Seungho Choi
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Nathan Buchweitz
- Department of Orthopedics, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Bioengineering, Clemson University, Clemson, SC 29634, USA
- Clemson-MUSC Joint Bioengineering Program, South Carolina, USA
| | - Hong Li
- Depatment of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Yongren Wu
- Department of Orthopedics, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Bioengineering, Clemson University, Clemson, SC 29634, USA
- Clemson-MUSC Joint Bioengineering Program, South Carolina, USA
| | - Hai Yao
- Department of Orthopedics, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Bioengineering, Clemson University, Clemson, SC 29634, USA
- Clemson-MUSC Joint Bioengineering Program, South Carolina, USA
- Department of Oral Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Shikhar Mehrotra
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Meenal Mehrotra
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Oral Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
- Center for Oral Health Research, Medical University of South Carolina, Charleston, SC 29425, USA
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23
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Lim SW, Shin YJ, Cui S, Ko EJ, Yoo SH, Chung BH, Yang CW. Therapeutic effect of multiple functional minicircle vector encoding anti-CD25/IL-10/CXCR3 in allograft rejection model. Korean J Intern Med 2022; 37:1031-1049. [PMID: 35725307 PMCID: PMC9449213 DOI: 10.3904/kjim.2021.299] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 01/04/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND/AIMS We previously proposed minicircle vector technology as the potential platform for the development and production of new biologics. In this study, we have designed a novel target molecule for the treatment of allograft rejection and evaluated its feasibility as the therapeutic agent in this disease using the minicircle vector system. METHODS We engineered vectors to carry cassette sequences for anti-CD25, interleukin-10 (IL-10), and C-X-C motif chemokine receptor 3 (CXCR3) fusion protein, and then isolated minicircle vectors from the parent vectors. We verified the substantial production of anti-CD25/IL-10/CXCR3 fusion protein from minicircles and their duration in HEK293T cells and mice models. We also evaluated whether minicircle-derived anti-CD25/IL-10/CXCR3 has therapeutic effects in a skin allograft in mice model. RESULTS We confirmed the production of anti-CD25/IL-10/CXCR3 from minicircle by its significant availability in cells transfected with the minicircle and in its conditioned media. After a single injection of minicircle by hydrodynamic injection via mouse tail vein, luminescence or red fluorescence was maintained until 40 days in the liver tissue, suggesting the production of anti-CD25/IL-10/CXCR3 protein from minicircles via protein synthesis machinery in the liver. Mice treated with the minicircle encoding anti-CD25/IL-10/CXCR3 showed prolonged skin allograft survival times accompanied by improved immunologic regulation e.g., reduction of the lymphocyte population of Th1, Th2, and Th17 and an induction of regulatory T cells. CONCLUSION These findings implied that self-generated anti-CD25/IL-10/CXCR3 protein drug by minicircle technology is functionally active and relevant for reducing allograft rejection. The minicircle vector system may be useful for developing new biological drugs, avoiding manufacturing or practical problems.
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Affiliation(s)
- Sun Woo Lim
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Yoo Jin Shin
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Sheng Cui
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Eun Jeong Ko
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | | | - Byung Ha Chung
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Chul Woo Yang
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
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24
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Wagner JC, Ronin E, Ho P, Peng Y, Tang Q. Anti-HLA-A2-CAR Tregs prolong vascularized mouse heterotopic heart allograft survival. Am J Transplant 2022; 22:2237-2245. [PMID: 35434896 PMCID: PMC9427704 DOI: 10.1111/ajt.17063] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/22/2022] [Accepted: 04/12/2022] [Indexed: 01/25/2023]
Abstract
Alloantigen-specific regulatory T cell (Treg) therapy is a promising approach for suppressing alloimmune responses and minimizing immunosuppression after solid organ transplantation. Chimeric antigen receptor (CAR) targeting donor alloantigens can confer donor reactivity to Tregs. However, CAR Treg therapy has not been evaluated in vascularized transplant or multi-MHC mismatched models. Here, we evaluated the ability of CAR Tregs targeting HLA-A2 (A2-CAR) to prolong the survival of heterotopic heart transplants in mice. After verifying the in vitro activation, proliferation, and enhanced suppressive function of A2-CAR Tregs in the presence of A2-antigen, we analyzed the in vivo function of Tregs in C57BL/6 (B6) mice receiving A2-expressing heart allografts. A2-CAR Treg infusion increased the median survival of grafts from B6.HLA-A2 transgenic donors from 23 to 99 days, whereas median survival with polyclonal Treg infusion was 35 days. In a more stringent model of haplo-mismatched hearts from BALB/cxB6.HLA-A2 F1 donors, A2-CAR Tregs slightly increased median graft survival from 11 to 14 days, which was further extended to >100 days when combined with a 9-day course of rapamycin treatment. These findings demonstrate the efficacy of CAR Tregs, alone or in combination with immunosuppressive agents, toward protecting vascularized grafts in fully immunocompetent recipients.
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Affiliation(s)
- Johanna C. Wagner
- Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA
| | - Emilie Ronin
- Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA
| | - Patrick Ho
- Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA
| | - Yani Peng
- Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA
| | - Qizhi Tang
- Department of Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA
- Gladstone-UCSF Institute of Genomic Immunology, 513 Parnassus Ave, San Francisco, CA 94143, USA
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25
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Mittal SK, Cho W, Elbasiony E, Guan Y, Foulsham W, Chauhan SK. Mesenchymal stem cells augment regulatory T cell function via CD80-mediated interactions and promote allograft survival. Am J Transplant 2022; 22:1564-1577. [PMID: 35170213 PMCID: PMC11261724 DOI: 10.1111/ajt.17001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 01/25/2022] [Accepted: 02/09/2022] [Indexed: 02/05/2023]
Abstract
Mesenchymal stem cells (MSCs) and regulatory T cells (Tregs) both have been shown to modulate the alloimmune response and promote transplant survival. Mounting evidence suggests that MSCs augment Treg function, but the mechanisms underlying this phenomenon have not been fully deciphered. Here, we identified that MSCs express substantial levels of CD80 and evaluated its immunoregulatory function using in vivo and in vitro experiments. Our in vitro culture assays demonstrated that MSCs induce expression of FoxP3 in Tregs in a contact-dependent manner, and the blockade of CD80 abrogates this FoxP3 induction and Treg-mediated suppression of T cell proliferation. Moreover, supplementation of soluble CD80 significantly upregulated FoxP3 expression. Using a well-characterized murine model of corneal transplantation, we show that silencing CD80 in MSCs diminishes the capacity of MSCs to promote selective graft infiltration of Tregs, promote FoxP3 expression and upregulate suppressive function of Tregs. Consequently, MSCs, following CD80 knockdown, failed to promote corneal allograft survival.
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Affiliation(s)
- Sharad K Mittal
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - WonKyung Cho
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - Elsayed Elbasiony
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - Yilin Guan
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - William Foulsham
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - Sunil K Chauhan
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
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26
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Role of T Regulatory Cells and Myeloid-Derived Suppressor Cells in COVID-19. J Immunol Res 2022; 2022:5545319. [PMID: 35497875 PMCID: PMC9042623 DOI: 10.1155/2022/5545319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/13/2022] [Accepted: 03/28/2022] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) has been raised as a pandemic disease since December 2019. Immunosuppressive cells including T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are key players in immunological tolerance and immunoregulation; however, they contribute to the pathogenesis of different diseases including infections. Tregs have been shown to impair the protective role of CD8+ T lymphocytes against viral infections. In COVID-19 patients, most studies reported reduction, while few other studies found elevation in Treg levels. Moreover, Tregs have a dual role, depending on the different stages of COVID-19 disease. At early stages of COVID-19, Tregs have a critical role in decreasing antiviral immune responses, and consequently reducing the viral clearance. On the other side, during late stages, Tregs reduce inflammation-induced organ damage. Therefore, inhibition of Tregs in early stages and their expansion in late stages have potentials to improve clinical outcomes. In viral infections, MDSC levels are highly increased, and they have the potential to suppress T cell proliferation and reduce viral clearance. Some subsets of MDSCs are expanded in the blood of COVID-19 patients; however, there is a controversy whether this expansion has pathogenic or protective effects in COVID-19 patients. In conclusion, further studies are required to investigate the role and function of immunosuppressive cells and their potentials as prognostic biomarkers and therapeutic targets in COVID-19 patients.
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27
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Lapp MM, Lin G, Komin A, Andrews L, Knudson M, Mossman L, Raimondi G, Arciero JC. Modeling the Potential of Treg-Based Therapies for Transplant Rejection: Effect of Dose, Timing, and Accumulation Site. Transpl Int 2022; 35:10297. [PMID: 35479106 PMCID: PMC9035492 DOI: 10.3389/ti.2022.10297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 03/17/2022] [Indexed: 02/04/2023]
Abstract
Introduction: The adoptive transfer of regulatory T cells (Tregs) has emerged as a method to promote graft tolerance. Clinical trials have demonstrated the safety of adoptive transfer and are now assessing their therapeutic efficacy. Strategies that generate large numbers of antigen specific Tregs are even more efficacious. However, the combinations of factors that influence the outcome of adoptive transfer are too numerous to be tested experimentally. Here, mathematical modeling is used to predict the most impactful treatment scenarios. Methods: We adapted our mathematical model of murine heart transplant rejection to simulate Treg adoptive transfer and to correlate therapeutic efficacy with Treg dose and timing, frequency of administration, and distribution of injected cells. Results: The model predicts that Tregs directly accumulating to the graft are more protective than Tregs localizing to draining lymph nodes. Inhibiting antigen-presenting cell maturation and effector functions at the graft site was more effective at modulating rejection than inhibition of T cell activation in lymphoid tissues. These complex dynamics define non-intuitive relationships between graft survival and timing and frequency of adoptive transfer. Conclusion: This work provides the framework for better understanding the impact of Treg adoptive transfer and will guide experimental design to improve interventions.
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Affiliation(s)
- Maya M. Lapp
- Department of Mathematics, The College of Wooster, Wooster, OH, United States
| | - Guang Lin
- Department of Mathematics, Purdue University, West Lafayette, IN, United States
| | - Alexander Komin
- Department of Plastic and Reconstructive Surgery, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Leah Andrews
- Department of Mathematics, St. Olaf College, Northfield, MN, United States
| | - Mei Knudson
- Department of Mathematics, Carleton College, Northfield, MN, United States
| | - Lauren Mossman
- Department of Mathematics, St. Olaf College, Northfield, MN, United States
| | - Giorgio Raimondi
- Department of Plastic and Reconstructive Surgery, Johns Hopkins School of Medicine, Baltimore, MD, United States,*Correspondence: Giorgio Raimondi, ; Julia C. Arciero,
| | - Julia C. Arciero
- Department of Mathematical Sciences, Indiana University-Purdue University of Indianapolis, Indianapolis, IN, United States,*Correspondence: Giorgio Raimondi, ; Julia C. Arciero,
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28
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Tripathi S, Martin-Moreno PL, Kavalam G, Schreiber BL, Waaga-Gasser AM, Chandraker A. Adenosinergic Pathway and Linked Suppression: Two Critical Suppressive Mechanisms of Human Donor Antigen Specific Regulatory T Cell Lines Expanded Post Transplant. Front Immunol 2022; 13:849939. [PMID: 35371066 PMCID: PMC8968184 DOI: 10.3389/fimmu.2022.849939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/18/2022] [Indexed: 11/13/2022] Open
Abstract
Regulatory T cells are an important component of an immune response shaping the overall behavior to potential antigens including alloantigens. Multiple mechanisms have been shown to contribute towards developing and sustaining a immunological regulatory response. One of the described contact dependent suppressive mechanisms regulatory cells have been shown to utilize is through the production of adenosine from extracellular ATP mediated by CD39 and CD73. In this study we demonstrate that the adenosinergic pathway plays a major role in the suppressive/regulatory effects antigen specific regulatory T cell enriched lines (ASTRLs) that have been of expanded ex vivo from stable kidney transplant patients. We have previously shown that these ASTRL cells are capable of suppressing alloimmune responses in vitro and significantly prolonging allograft survival in an animal model of kidney transplantation. For this study nineteen ASTRLs were expanded from 17 kidney transplant patients by repeated stimulation of recipient peripheral blood mononuclear cells with donor specific HLA-DR peptides. All 19 ASTRLs showed upregulation of numerous markers associated with regulatory cells and were able to inhibit donor antigen specific T cell proliferation in a dose dependent fashion. ASTRLs suppressed indirect and direct alloimmune responses compatible with our previous animal study findings. Upregulation of both CD39 and CD73 was observed post expansion and ASTRLs demonstrated extracellular hydrolysis of ATP, indicating functionality of the upregulated proteins. We also showed that inhibition of the adenosinergic pathway using inhibitors of CD39 resulted in abrogation of suppression and increased antigen specific T cell proliferation. This demonstrates that the main mechanism of action of the suppressive activity donor peptide driven ASTRLs generated from kidney transplant patients is the adenosinergic pathway. Furthermore this suggests the possibility that combining infusion of Tregs with other treatments, such as adenosine receptor agonists or increasing CD39 expression in the grafts may further enhance a regulatory response to the allograft and possibly achieve transplantation tolerance.
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Affiliation(s)
- Sudipta Tripathi
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Paloma L Martin-Moreno
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.,Nephrology Department, Clinica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - George Kavalam
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Brittany L Schreiber
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Ana Maria Waaga-Gasser
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Anil Chandraker
- Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
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29
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Skartsis N, Peng Y, Ferreira LMR, Nguyen V, Ronin E, Muller YD, Vincenti F, Tang Q. IL-6 and TNFα Drive Extensive Proliferation of Human Tregs Without Compromising Their Lineage Stability or Function. Front Immunol 2022; 12:783282. [PMID: 35003100 PMCID: PMC8732758 DOI: 10.3389/fimmu.2021.783282] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 11/29/2021] [Indexed: 01/09/2023] Open
Abstract
Treg therapies are being tested in clinical trials in transplantation and autoimmune diseases, however, the impact of inflammation on Tregs remains controversial. We challenged human Tregs ex-vivo with pro-inflammatory cytokines IL-6 and TNFα and observed greatly enhanced proliferation stimulated by anti-CD3 and anti-CD28 (aCD3/28) beads or CD28 superagonist (CD28SA). The cytokine-exposed Tregs maintained high expression of FOXP3 and HELIOS, demethylated FOXP3 enhancer, and low IFNγ, IL-4, and IL-17 secretion. Blocking TNF receptor using etanercept or deletion of TNF receptor 2 using CRISPR/Cas9 blunted Treg proliferation and attenuated FOXP3 and HELIOS expression. These results prompted us to consider using CD28SA together with IL-6 and TNFα without aCD3/28 beads (beadless) as an alternative protocol for therapeutic Treg manufacturing. Metabolomics profiling revealed more active glycolysis and oxidative phosphorylation, increased energy production, and higher antioxidant potential during beadless Treg expansion. Finally, beadless expanded Tregs maintained suppressive functions in vitro and in vivo. These results demonstrate that human Tregs positively respond to proinflammatory cytokines with enhanced proliferation without compromising their lineage identity or function. This property can be harnessed for therapeutic Treg manufacturing.
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Affiliation(s)
- Nikolaos Skartsis
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States.,Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA, United States
| | - Yani Peng
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Leonardo M R Ferreira
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Vinh Nguyen
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Emilie Ronin
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Yannick D Muller
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Flavio Vincenti
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States.,Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA, United States
| | - Qizhi Tang
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States.,Diabetes Center, University of California San Francisco, San Francisco, CA, United States
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30
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Mesenchymal stem cells transfer mitochondria to allogeneic Tregs in an HLA-dependent manner improving their immunosuppressive activity. Nat Commun 2022; 13:856. [PMID: 35165293 PMCID: PMC8844425 DOI: 10.1038/s41467-022-28338-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/18/2022] [Indexed: 12/15/2022] Open
Abstract
Cell-based immunotherapies can provide safe and effective treatments for various disorders including autoimmunity, cancer, and excessive proinflammatory events in sepsis or viral infections. However, to achieve this goal there is a need for deeper understanding of mechanisms of the intercellular interactions. Regulatory T cells (Tregs) are a lymphocyte subset that maintain peripheral tolerance, whilst mesenchymal stem cells (MSCs) are multipotent nonhematopoietic progenitor cells. Despite coming from different origins, Tregs and MSCs share immunoregulatory properties that have been tested in clinical trials. Here we demonstrate how direct and indirect contact with allogenic MSCs improves Tregs’ potential for accumulation of immunosuppressive adenosine and suppression of conventional T cell proliferation, making them more potent therapeutic tools. Our results also demonstrate that direct communication between Tregs and MSCs is based on transfer of active mitochondria and fragments of plasma membrane from MSCs to Tregs, an event that is HLA-dependent and associates with HLA-C and HLA-DRB1 eplet mismatch load between Treg and MSC donors. Regulatory T (Treg) cells and mesenchymal stem cells (MSCs) are both cell populations capable of immune tolerance induction. Here the authors show that the transfer of mitochondria from mesenchymal stem cells to allogeneic Treg cells in an HLA-dependent manner results in enhanced immunosuppressive functions of Treg cells.
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31
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Bottomley MJ, Brook MO, Shankar S, Hester J, Issa F. Towards regulatory cellular therapies in solid organ transplantation. Trends Immunol 2022; 43:8-21. [PMID: 34844848 DOI: 10.1016/j.it.2021.11.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 10/10/2021] [Accepted: 11/01/2021] [Indexed: 01/03/2023]
Abstract
Organ transplantation is a modern medical success story. However, since its inception it has been limited by the need for pharmacological immunosuppression. Regulatory cellular therapies offer an attractive solution to these challenges by controlling transplant alloresponses through multiple parallel suppressive mechanisms. A number of cell types have seen an accelerated development into human trials and are now on the threshold of a long-awaited breakthrough in personalized transplant therapeutics. Here we assess recent developments with a focus on the most likely candidates, some of which have already facilitated successful immunosuppression withdrawal in early clinical trials. We propose that this may constitute a promising approach in clinical transplantation but also evaluate outstanding issues in the field, providing cause for cautious optimism.
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Affiliation(s)
- Matthew J Bottomley
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Oxford Transplant Centre, Churchill Hospital, Oxford, UK
| | - Matthew O Brook
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Oxford Transplant Centre, Churchill Hospital, Oxford, UK
| | - Sushma Shankar
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Oxford Transplant Centre, Churchill Hospital, Oxford, UK
| | - Joanna Hester
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Fadi Issa
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
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32
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Balcerek J, Shy BR, Putnam AL, Masiello LM, Lares A, Dekovic F, Acevedo L, Lee MR, Nguyen V, Liu W, Paruthiyil S, Xu J, Leinbach AS, Bluestone JA, Tang Q, Esensten JH. Polyclonal Regulatory T Cell Manufacturing Under cGMP: A Decade of Experience. Front Immunol 2021; 12:744763. [PMID: 34867967 PMCID: PMC8636860 DOI: 10.3389/fimmu.2021.744763] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 11/01/2021] [Indexed: 12/29/2022] Open
Abstract
We report on manufacturing outcomes for 41 autologous polyclonal regulatory T cell (PolyTreg) products for 7 different Phase 1 clinical trials over a 10-year period (2011-2020). Data on patient characteristics, manufacturing parameters, and manufacturing outcomes were collected from manufacturing batch records and entered into a secure database. Overall, 88% (36/41) of PolyTreg products met release criteria and 83% (34/41) of products were successfully infused into patients. Of the 7 not infused, 5 failed release criteria, and 2 were not infused because the patient became ineligible due to a change in clinical status. The median fold expansion over the 14-day manufacturing process was 434.8 -fold (range 29.8-2,232), resulting in a median post-expansion cell count of 1,841 x 106 (range 56.9-16,179 x 106). The main correlate of post-expansion cell number was starting cell number, which positively correlates with absolute circulating Treg cell count. Other parameters, including date of PolyTreg production, patient sex, and patient age did not significantly correlate with fold expansion of Treg during product manufacturing. In conclusion, PolyTreg manufacturing outcomes are consistent across trials and dates of production.
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Affiliation(s)
- Joanna Balcerek
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, United States
| | - Brian R Shy
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, United States
| | - Amy L Putnam
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States
| | - Lisa M Masiello
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States
| | - Angela Lares
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States
| | - Florinna Dekovic
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States
| | - Luis Acevedo
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States
| | - Michael R Lee
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States
| | - Vinh Nguyen
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Weihong Liu
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States
| | - Sreenivasan Paruthiyil
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States
| | - Jingying Xu
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States
| | - Ashley S Leinbach
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States
| | - Jeffrey A Bluestone
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States.,Sean N. Parker Autoimmune Research Laboratory, University of California San Francisco, San Francisco, CA, United States
| | - Qizhi Tang
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States.,Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Jonathan H Esensten
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, United States
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33
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Bian J, Wang T, Sun J, He X, Wu Z, Zhang S, Chi H, Fan T, Wang S, Shi W, Ruan Q. Targeting NF-κB c-Rel in regulatory T cells to treat corneal transplantation rejection. Am J Transplant 2021; 21:3858-3870. [PMID: 34254428 DOI: 10.1111/ajt.16760] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 07/05/2021] [Accepted: 07/08/2021] [Indexed: 01/25/2023]
Abstract
The relevance of Tregs in the induction of tolerance against corneal allografts has been well established. Although it is well known that the conversion of Tregs into effector-like cells contributes to the loss of corneal immune privilege, the underlying mechanism is still not fully understood. Using heterologous penetrating keratoplasty model, we found that Tregs from corneal allograft rejected mice (inflam-Tregs) exhibit impaired function and characteristics of effector T cells. Further study showed that the expression of NF-κB c-Rel, a key mediator of effector T cell function, was significantly increased in inflam-Tregs. Mechanistic study revealed that elevated NF-κB c-Rel level in inflam-Tregs impaired Treg function through the promotion of inflammatory cytokine production and glycolysis. More importantly, we demonstrated that targeting NF-κB c-Rel was able to improve the immune suppressive function of inflam-Tregs in vitro and enhance the potential of them to suppress corneal transplantation rejection. Therefore, our current study identified NF-κB c-Rel as a key mediator of the conversion of Tregs into effector-like cells when under inflammatory environment.
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Affiliation(s)
- Jiang Bian
- Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China
| | - Ting Wang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China.,Eye Hospital of Shandong First Medical University, Jinan, China
| | - Jijun Sun
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China.,Eye Hospital of Shandong First Medical University, Jinan, China
| | - Xiaozhen He
- Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China
| | - Zhijiao Wu
- Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China
| | - Songmei Zhang
- Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China
| | - Hao Chi
- Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China
| | - Tingting Fan
- Center for Antibody Drug, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Shaowen Wang
- Center for Antibody Drug, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Weiyun Shi
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China.,Eye Hospital of Shandong First Medical University, Jinan, China
| | - Qingguo Ruan
- Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China.,Center for Antibody Drug, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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34
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Tian W, Jiang SY, Jiang X, Tamosiuniene R, Kim D, Guan T, Arsalane S, Pasupneti S, Voelkel NF, Tang Q, Nicolls MR. The Role of Regulatory T Cells in Pulmonary Arterial Hypertension. Front Immunol 2021; 12:684657. [PMID: 34489935 PMCID: PMC8418274 DOI: 10.3389/fimmu.2021.684657] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 08/04/2021] [Indexed: 01/10/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a chronic, incurable condition characterized by pulmonary vascular remodeling, perivascular inflammation, and right heart failure. Regulatory T cells (Tregs) stave off autoimmunity, and there is increasing evidence for their compromised activity in the inflammatory milieu of PAH. Abnormal Treg function is strongly correlated with a predisposition to PAH in animals and patients. Athymic Treg-depleted rats treated with SU5416, an agent causing pulmonary vascular injury, develop PAH, which is prevented by infusing missing CD4+CD25highFOXP3+ Tregs. Abnormal Treg activity may also explain why PAH disproportionately affects women more than men. This mini review focuses on the role of Tregs in PAH with a special view to sexual dimorphism and the future promise of Treg therapy.
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Affiliation(s)
- Wen Tian
- Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA, United States
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Shirley Y. Jiang
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Xinguo Jiang
- Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA, United States
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Rasa Tamosiuniene
- Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA, United States
| | - Dongeon Kim
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Torrey Guan
- Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA, United States
| | - Siham Arsalane
- Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA, United States
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Shravani Pasupneti
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Norbert F. Voelkel
- Department of Pulmonary Medicine, Amsterdam University Medical Centers, Amsterdam, Netherlands
| | - Qizhi Tang
- Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Mark R. Nicolls
- Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA, United States
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
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35
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Dong S, Hiam-Galvez KJ, Mowery CT, Herold KC, Gitelman SE, Esensten JH, Liu W, Lares AP, Leinbach AS, Lee M, Nguyen V, Tamaki SJ, Tamaki W, Tamaki CM, Mehdizadeh M, Putnam AL, Spitzer MH, Ye CJ, Tang Q, Bluestone JA. The effects of low-dose IL-2 on Treg adoptive cell therapy in patients with Type 1 diabetes. JCI Insight 2021; 6:e147474. [PMID: 34324441 PMCID: PMC8492314 DOI: 10.1172/jci.insight.147474] [Citation(s) in RCA: 112] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 07/28/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND A previous phase I study showed that the infusion of autologous Tregs expanded ex vivo into patients with recent-onset type 1 diabetes (T1D) had an excellent safety profile. However, the majority of the infused Tregs were undetectable in the peripheral blood 3 months postinfusion (Treg-T1D trial). Therefore, we conducted a phase I study (TILT trial) combining polyclonal Tregs and low-dose IL-2, shown to enhance Treg survival and expansion, and assessed the impact over time on Treg populations and other immune cells. METHODS Patients with T1D were treated with a single infusion of autologous polyclonal Tregs followed by one or two 5-day courses of recombinant human low-dose IL-2 (ld-IL-2). Flow cytometry, cytometry by time of flight, and 10x Genomics single-cell RNA-Seq were used to follow the distinct immune cell populations’ phenotypes over time. RESULTS Multiparametric analysis revealed that the combination therapy led to an increase in the number of infused and endogenous Tregs but also resulted in a substantial increase from baseline in a subset of activated NK, mucosal associated invariant T, and clonal CD8+ T cell populations. CONCLUSION These data support the hypothesis that ld-IL-2 expands exogenously administered Tregs but also can expand cytotoxic cells. These results have important implications for the use of a combination of ld-IL-2 and Tregs for the treatment of autoimmune diseases with preexisting active immunity. TRIAL REGISTRATION ClinicalTrials.gov NCT01210664 (Treg-T1D trial), NCT02772679 (TILT trial). FUNDING Sean N. Parker Autoimmune Research Laboratory Fund, National Center for Research Resources.
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Affiliation(s)
- Shen Dong
- Diabetes Center, UCSF, San Francisco, United States of America
| | - Kamir J Hiam-Galvez
- Parker Institute for Cancer Immunotherapy, UCSF, San Francisco, United States of America
| | - Cody T Mowery
- Institute for Human Genetics, UCSF, San Francisco, United States of America
| | - Kevan C Herold
- Department of Immunobiology, Yale University School of Medicine, New Haven, United States of America
| | - Stephen E Gitelman
- Division Pediatric Endocrinology and Diabetes Center, UCSF, San Francisco, United States of America
| | - Jonathan H Esensten
- Department of Laboratory Medicine, UCSF, San Francisco, United States of America
| | - Weihong Liu
- Diabetes Center, UCSF, San Francisco, United States of America
| | - Angela P Lares
- Diabetes Center, UCSF, San Francisco, United States of America
| | | | - Michael Lee
- Diabetes Center, UCSF, San Francisco, United States of America
| | - Vinh Nguyen
- Diabetes Center, UCSF, San Francisco, United States of America
| | - Stanley J Tamaki
- Flow Cytometry Core Parnassus, UCSF, San Francisco, United States of America
| | - Whitney Tamaki
- Diabetes Center, UCSF, San Francisco, United States of America
| | | | | | - Amy L Putnam
- Diabetes Center, UCSF, San Francisco, United States of America
| | - Matthew H Spitzer
- Department of Otolaryngology, UCSF, San Francisco, United States of America
| | - C Jimmie Ye
- Institute for Human Genetics, UCSF, San Francisco, United States of America
| | - Qizhi Tang
- Division of Transplant Surgery, UCSF, San Francisco, United States of America
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36
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Targeting immunosuppressor cells with nanoparticles in autoimmunity: How far have we come to? Cell Immunol 2021; 368:104412. [PMID: 34340162 DOI: 10.1016/j.cellimm.2021.104412] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 12/24/2022]
Abstract
Autoimmunity is the assault of immune response towards self-antigens, resulting to inflammation and tissue injury. It is staged into three phases and caused by malfunction of immune tolerance. In our body, immune tolerance is synchronized by several immunosuppressor cells such as regulatory T cells and B cells as well as myeloid-derived suppressor cells, which are prominently dysregulated in autoimmunity. Hence, targeting these cell populations serve as a significant potential in the therapy of autoimmunity. Nanotechnology with its advantageous properties is shown to be a remarkable tool as drug delivery system in this field. This review focused on the development of therapeutics in autoimmune diseases utilizing various nanoparticles formulation based on two targeting approaches in autoimmunity, passive and active targeting. Lastly, this review outlined the approved present nanomedicines as well as in clinical evaluations and issues regarding the lack of translation of these nanomedicines into the market, despite the abundant of positive experimental observations.
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37
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Petrus-Reurer S, Romano M, Howlett S, Jones JL, Lombardi G, Saeb-Parsy K. Immunological considerations and challenges for regenerative cellular therapies. Commun Biol 2021; 4:798. [PMID: 34172826 PMCID: PMC8233383 DOI: 10.1038/s42003-021-02237-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 05/17/2021] [Indexed: 02/06/2023] Open
Abstract
The central goal of regenerative medicine is to replace damaged or diseased tissue with cells that integrate and function optimally. The capacity of pluripotent stem cells to produce unlimited numbers of differentiated cells is of considerable therapeutic interest, with several clinical trials underway. However, the host immune response represents an important barrier to clinical translation. Here we describe the role of the host innate and adaptive immune responses as triggers of allogeneic graft rejection. We discuss how the immune response is determined by the cellular therapy. Additionally, we describe the range of available in vitro and in vivo experimental approaches to examine the immunogenicity of cellular therapies, and finally we review potential strategies to ameliorate immune rejection. In conclusion, we advocate establishment of platforms that bring together the multidisciplinary expertise and infrastructure necessary to comprehensively investigate the immunogenicity of cellular therapies to ensure their clinical safety and efficacy.
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Affiliation(s)
- Sandra Petrus-Reurer
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
| | - Marco Romano
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom
| | - Sarah Howlett
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Joanne Louise Jones
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom
| | - Kourosh Saeb-Parsy
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
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38
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Lee WC, Wang YC, Hsu HY, Hsu PY, Cheng CH, Lee CF, Wu TJ, Chan KM. Immunological discrepancy in aged mice facilitates skin allograft survival. Aging (Albany NY) 2021; 13:16219-16228. [PMID: 34157682 PMCID: PMC8266325 DOI: 10.18632/aging.203152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 05/14/2021] [Indexed: 04/29/2023]
Abstract
More and more aged people are undergoing organ transplantation. Understanding aging effects on immunity will be helpful for post-transplantation care and adjustment of immunosuppressants for aged recipients. A mouse model, using C3H mice as donors and aged/young C57BL/10J mice as recipients, was employed to study aging effects on immunity. The results showed that frequency of myeloid-derived suppressor cells (MDSC) and level of TGF-β was higher in aged mice than in young mice (4.4 ± 1.4% versus 1.6 ± 1.1%, p = 0.026 for MDSC; 21.04 ± 3.91 ng/ml versus 15.26 ± 5.01 ng/ml, p = 0.026 for TGF-β). In vivo, skin allograft survived longer on the aged than on young mice (19.7 ± 5.2 days versus 11.9 ± 4.1 days, p = 0.005). When entinostat was applied to block MDSC, the survival of skin allografts on aged mice was shorten to 13.5 ± 4.7 days which was not different from the survival on young mice (p = 0.359). In conclusion, allogeneic immunity was different in aged from young mice in high frequency of MDSC and high serum level of TGF-β. Blocking the function of MDSC reversed the low immunity in aged mice and caused skin allograft rejection similar to young recipients.
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Affiliation(s)
- Wei-Chen Lee
- Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Yu-Chao Wang
- Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Hsiu-Ying Hsu
- Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Pao-Yueh Hsu
- Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Chih-Hsien Cheng
- Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Chen-Fang Lee
- Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Ting-Jung Wu
- Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Kun-Ming Chan
- Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan
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39
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Ni X, Wang Q, Gu J, Lu L. Clinical and Basic Research Progress on Treg-Induced Immune Tolerance in Liver Transplantation. Front Immunol 2021; 12:535012. [PMID: 34093514 PMCID: PMC8173171 DOI: 10.3389/fimmu.2021.535012] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 04/26/2021] [Indexed: 12/29/2022] Open
Abstract
Rejection after organ transplantation is a cause of graft failure. Effectively reducing rejection and inducing tolerance is a challenge in the field of transplantation immunology. The liver, as an immunologically privileged organ, has high rates of spontaneous and operational tolerance after transplantation, allowing it to maintain its normal function for long periods. Although modern immunosuppression regimens have serious toxicity and side effects, it is very risky to discontinue immunosuppression regimens blindly. A more effective treatment to induce immune tolerance is the most sought-after goal in transplant medicine. Tregs have been shown to play a pivotal role in the regulation of immune balance, and infusion of Tregs can also effectively prevent rejection and cure autoimmune diseases without significant side effects. Given the immune characteristics of the liver, the correct use of Tregs can more effectively induce the occurrence of operational tolerance for liver transplants than for other organ transplants. This review mainly summarizes the latest research advances regarding the characteristics of the hepatic immune microenvironment, operational tolerance, Treg generation in vitro, and the application of Tregs in liver transplantation. It is hoped that this review will provide a deeper understanding of Tregs as the most effective treatment to induce and maintain operational tolerance after liver transplantation.
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Affiliation(s)
- Xuhao Ni
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Qi Wang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Jian Gu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Ling Lu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
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40
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Waldmann H. Regulatory T cells and transplantation tolerance: Emerging from the darkness? Eur J Immunol 2021; 51:1580-1591. [PMID: 33961297 DOI: 10.1002/eji.202048795] [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] [Received: 01/18/2021] [Revised: 03/29/2021] [Accepted: 05/05/2021] [Indexed: 12/11/2022]
Abstract
The field of tissue transplantation has revolutionized the treatment of patients with failing organs. Its success, thus far, has depended on combinations of immunosuppressive drugs that damp host immunity, while also imposing numerous unwanted side-effects. There is a longstanding recognition that better treatment outcomes, will come from replacing these drugs, fully or in part, by taking advantage of tractable physiological mechanisms of self-tolerance. The past 50 years have seen many advances in the field of self-tolerance, but perhaps, the most tractable of these has been the more recent discovery of a subset T-cells (Treg) whose role is to regulate or damp immunity. This article is intended to first provide the reader with some historical background to explain why we have been slow to identify these cells, despite numerous clues to their existence, and also to indicate how little we know about how they achieve their regulatory function in averting transplant rejection. However, as is often the case in immunology, the therapeutic needs often dictate that our advances move to translation even before detailed explanations of the science are available. The final part of the article will briefly summarize how Treg are being harnessed as agents to interface with or perhaps, replace current drug combinations.
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Affiliation(s)
- Herman Waldmann
- Sir William Dunn School, University of Oxford, Oxford, OX13RE, UK
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41
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Jahromi M, Al-Otaibi T, Ashry Gheith O, Farouk Othman N, Mahmoud T, Nair P, A-Halim M, Aggarwal P, Messenger G, Chu P, De Serres SA, Azzi JR. Analysis of the frequency of single nucleotide polymorphisms in cytokine genes in patients with New Onset Diabetes After Transplant. Sci Rep 2021; 11:6014. [PMID: 33727573 PMCID: PMC7966742 DOI: 10.1038/s41598-021-84400-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 01/13/2021] [Indexed: 12/03/2022] Open
Abstract
New Onset Diabetes After Transplantation (NODAT) is a serious metabolic complication. While β-cell dysfunction is considered the main contributing factor in the development of NODAT, the precise pathogenesis is not well understood. Cytokines are thought to be involved in the inflammation of islet β-cells in diabetes; however, few studies have investigated this hypothesis in NODAT. A total of 309 kidney transplant recipients (KTRs) were included in this study. An association between kidney transplants, and the development of diabetes after transplant (NODAT) was investigated. Comparison was made between KTRs who develop diabetes (NODAT cases) or did not develop diabetes (control), using key cytokines, IL-6 G (- 174)C, macrophage mediator; IL-4 C (- 490)T, T helper (Th)-2 cytokine profile initiator; Th-1 cytokine profile initiator interferon-γ T (+ 874) A gene and TGF β1 C (+ 869) T gene polymorphisms were investigated. The genes were amplified using well-established polymerase chain reaction (PCR) techniques in our laboratory. Compared to the AA and AT genotypes of interferon gamma (IFNG), there was a strong association between the TT genotype of IFNG and NODAT kidney transplant recipients (KTRs) versus non-NODAT KTRs (p = 0.005). The AA genotype of IFNG was found to be predominant in the control group (p = 0.004). Also, significant variations of IL6 G (- 174) C, IL-4 C (- 590) T, interferon-γ T (+ 874) A gene and transforming growth factor β1 C (+ 869) T may contribute to NODAT. Our data is consistent with theTh-1/T-reg pathway of immunity. Further larger pan Arab studies are required to confirm our findings.
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Affiliation(s)
- Mohamed Jahromi
- Clinical Research, Medical Division, Dasman Diabetes Institute, Kuwait City, Kuwait.
- Sehatek Awal, Manama, Bahrain.
| | - Torki Al-Otaibi
- Nephrology Department, Hamad Al-Essa Organ Transplantation Center, Kuwait City, Kuwait
| | - Osama Ashry Gheith
- Nephrology Department, Hamad Al-Essa Organ Transplantation Center, Kuwait City, Kuwait
- Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Nashwa Farouk Othman
- Community department, Faculty of Nursing, Manoura University, Mansoura, Egypt
- Education, Clinical Services Division, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Tarek Mahmoud
- Nephrology Department, Hamad Al-Essa Organ Transplantation Center, Kuwait City, Kuwait
| | - Parasad Nair
- Nephrology Department, Hamad Al-Essa Organ Transplantation Center, Kuwait City, Kuwait
| | - Medhat A-Halim
- Nephrology Department, Hamad Al-Essa Organ Transplantation Center, Kuwait City, Kuwait
| | | | - Grace Messenger
- Podiatry Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | | | | | - Jamil R Azzi
- Kidney Division, Transplantation Research Center, Harvard Medical School, Brigham and Women's Hospital, Boston, USA
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Zhou JY, Alvarez CA, Cobb BA. Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy. eLife 2021; 10:e57417. [PMID: 33617447 PMCID: PMC7899647 DOI: 10.7554/elife.57417] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 01/20/2021] [Indexed: 12/14/2022] Open
Abstract
Cells exist within complex milieus of communicating factors, such as cytokines, that combine to generate context-specific responses, yet nearly all knowledge about the function of each cytokine and the signaling propagated downstream of their recognition is based on the response to individual cytokines. Here, we found that regulatory T cells (Tregs) integrate concurrent signaling initiated by IL-2 and IL-4 to generate a response divergent from the sum of the two pathways in isolation. IL-4 stimulation of STAT6 phosphorylation was blocked by IL-2, while IL-2 and IL-4 synergized to enhance STAT5 phosphorylation, IL-10 production, and the selective proliferation of IL-10-producing Tregs, leading to increased inhibition of conventional T cell activation and the reversal of asthma and multiple sclerosis in mice. These data define a mechanism of combinatorial cytokine signaling and lay the foundation upon which to better understand the origins of cytokine pleiotropy while informing improved the clinical use of cytokines.
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Affiliation(s)
- Julie Y Zhou
- Department of Pathology, Case Western Reserve University School of MedicineClevelandUnited States
| | - Carlos A Alvarez
- Department of Pathology, Case Western Reserve University School of MedicineClevelandUnited States
| | - Brian A Cobb
- Department of Pathology, Case Western Reserve University School of MedicineClevelandUnited States
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Hwang JH, Piao H, Jang JY, Lee SK, Han D, Lee GM, Go C, Kim Y, Oh KI, Kang JS, Yan JJ, Yang J. Suppressive effects of vitamin C-treated induced-regulatory T cells on heart allograft rejection under vitamin C-deficient or -sufficient conditions. PLoS One 2021; 16:e0246967. [PMID: 33577562 PMCID: PMC7880463 DOI: 10.1371/journal.pone.0246967] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 01/28/2021] [Indexed: 12/30/2022] Open
Abstract
Foxp3 stability of vitamin C-treated induced-regulatory T cells (V-iTregs) is superior to that of conventional iTregs (C-iTregs). However, the role of V-iTregs in allograft rejection under vitamin C-deficient conditions, such as those seen in humans, remains unclear. We aimed to elucidate the role of vitamin C treatment on generation and maintenance of iTregs from gulo knockout (Gulo-KO) mice as well as wild type (WT) mice, and in vitro and in vivo suppressive effects of V-iTregs on heart allograft rejection in either Gulo-KO or WT recipient mice. Conversion efficiency of iTregs was similar between C- and V-iTregs in both WT and Gulo-KO mice. V-iTregs from WT or Gulo-KO mice showed better in vitro Foxp3 stability than C-iTregs, although there was no difference between WT V-iTregs and Gulo-KO V-iTregs. Furthermore, V-iTregs from WT or Gulo-KO mice suppressed in vitro T cell proliferation better than C-iTregs. Heterotrophic heart transplantation from BALB/c mice to WT or vitamin C-deficient Gulo-KO C57BL/6J mice was performed following adoptive transfer of C- or V-iTregs. V-iTregs as well as C-iTregs prolonged heart allograft survival in WT and Gulo-KO mice. However, there was no difference between the C- and V-iTreg groups. Supplementation of low- or high-dose vitamin C did not induce significant changes in heart allograft survival in Gulo-KO recipients that had received V-iTregs. In conclusion, V-iTregs do not exert better suppressive effects on heart allograft survival than C-iTregs in either WT or vitamin C-deficient recipients.
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Affiliation(s)
- Ju Hee Hwang
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Honglin Piao
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Medicine, Graduate School, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Joon Young Jang
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sun-Kyung Lee
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Medicine, Graduate School, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Dongkyu Han
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Gwang-Min Lee
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Cheolhyeon Go
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yejin Kim
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Kwon Ik Oh
- Department of Pathology, Hallym University College of Medicine, Chuncheon, Republic of Korea
| | - Jae Seung Kang
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Ji-Jing Yan
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jaeseok Yang
- Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea
- Department of surgery, Seoul National University hospital, Seoul, Republic of Korea
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44
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Bourgeois S, Sawatani T, Van Mulders A, De Leu N, Heremans Y, Heimberg H, Cnop M, Staels W. Towards a Functional Cure for Diabetes Using Stem Cell-Derived Beta Cells: Are We There Yet? Cells 2021; 10:cells10010191. [PMID: 33477961 PMCID: PMC7835995 DOI: 10.3390/cells10010191] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus is a pandemic metabolic disorder that results from either the autoimmune destruction or the dysfunction of insulin-producing pancreatic beta cells. A promising cure is beta cell replacement through the transplantation of islets of Langerhans. However, donor shortage hinders the widespread implementation of this therapy. Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, represent an attractive alternative beta cell source for transplantation. Although major advances over the past two decades have led to the generation of stem cell-derived beta-like cells that share many features with genuine beta cells, producing fully mature beta cells remains challenging. Here, we review the current status of beta cell differentiation protocols and highlight specific challenges that are associated with producing mature beta cells. We address the challenges and opportunities that are offered by monogenic forms of diabetes. Finally, we discuss the remaining hurdles for clinical application of stem cell-derived beta cells and the status of ongoing clinical trials.
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Affiliation(s)
- Stephanie Bourgeois
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Toshiaki Sawatani
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; (T.S.); (M.C.)
| | - Annelore Van Mulders
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Nico De Leu
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
- Department of Endocrinology, University Hospital Brussels, 1090 Brussels, Belgium
- Department of Endocrinology, ASZ Aalst, 9300 Aalst, Belgium
| | - Yves Heremans
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Harry Heimberg
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Miriam Cnop
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; (T.S.); (M.C.)
- Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - Willem Staels
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
- Service of Pediatric Endocrinology, Department of Pediatrics, KidZ Health Castle, Universitair Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium
- Correspondence: ; Tel.: +32-0-24774473
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45
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Roth-Walter F, Adcock IM, Benito-Villalvilla C, Bianchini R, Bjermer L, Boyman O, Caramori G, Cari L, Fan Chung K, Diamant Z, Eguiluz-Gracia I, Knol EF, Kolios A, Levi-Schaffer F, Nocentini G, Palomares O, Redegeld F, Van Esch B, Stellato C. Immune modulation via T regulatory cell enhancement: Disease-modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases-An EAACI position paper of the Task Force on Immunopharmacology (TIPCO). Allergy 2021; 76:90-113. [PMID: 32593226 DOI: 10.1111/all.14478] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 06/09/2020] [Accepted: 06/18/2020] [Indexed: 12/13/2022]
Abstract
Therapeutic advances using targeted biologicals and small-molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell-based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell-based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell-based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders.
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Affiliation(s)
- Franziska Roth-Walter
- Comparative Medicine, The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Vienna, Austria
| | - Ian M Adcock
- Molecular Cell Biology Group, National Heart & Lung Institute, Imperial College London, London, UK
| | - Cristina Benito-Villalvilla
- Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of Madrid, Madrid, Spain
| | - Rodolfo Bianchini
- Comparative Medicine, The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Vienna, Austria
| | - Leif Bjermer
- Department of Respiratory Medicine and Allergology, Lung and Allergy research, Allergy, Asthma and COPD Competence Center, Lund University, Lund, Sweden
| | - Onur Boyman
- Department of Immunology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Gaetano Caramori
- Department of Biomedical Sciences, Dentistry and Morphological and Functional Imaging (BIOMORF), Respiratory Medicine Unit, University of Messina, Messina, Italy
| | - Luigi Cari
- Department of Medicine, Section of Pharmacology, University of Perugia, Perugia, Italy
| | - Kian Fan Chung
- Experimental Studies Medicine at National Heart & Lung Institute, Imperial College London & Royal Brompton & Harefield NHS Trust, London, UK
| | - Zuzana Diamant
- Department of Respiratory Medicine and Allergology, Institute for Clinical Science, Skane University Hospital, Lund, Sweden
- Department of Respiratory Medicine, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic
- Department of Clinical Pharmacy & Pharmacology, University Groningen, University Medical Center Groningen and QPS-NL, Groningen, Netherlands
| | - Ibon Eguiluz-Gracia
- Allergy Unit, Hospital Regional Universitario de Málaga-Instituto de Investigación Biomédica de Málaga (IBIMA)-ARADyAL, Málaga, Spain
| | - Edward F Knol
- Departments of Immunology and Dermatology/Allergology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Antonios Kolios
- Department of Immunology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Francesca Levi-Schaffer
- Pharmacology Unit, Faculty of Medicine, Institute for Drug Research, The Hebrew University of Jerusalem, Israel
| | - Giuseppe Nocentini
- Department of Medicine, Section of Pharmacology, University of Perugia, Perugia, Italy
| | - Oscar Palomares
- Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of Madrid, Madrid, Spain
| | - Frank Redegeld
- Faculty of Science, Division of Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Betty Van Esch
- Faculty of Science, Division of Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Cristiana Stellato
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy
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46
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Tahbaz M, Yoshihara E. Immune Protection of Stem Cell-Derived Islet Cell Therapy for Treating Diabetes. Front Endocrinol (Lausanne) 2021; 12:716625. [PMID: 34447354 PMCID: PMC8382875 DOI: 10.3389/fendo.2021.716625] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/19/2021] [Indexed: 12/14/2022] Open
Abstract
Insulin injection is currently the main therapy for type 1 diabetes (T1D) or late stage of severe type 2 diabetes (T2D). Human pancreatic islet transplantation confers a significant improvement in glycemic control and prevents life-threatening severe hypoglycemia in T1D patients. However, the shortage of cadaveric human islets limits their therapeutic potential. In addition, chronic immunosuppression, which is required to avoid rejection of transplanted islets, is associated with severe complications, such as an increased risk of malignancies and infections. Thus, there is a significant need for novel approaches to the large-scale generation of functional human islets protected from autoimmune rejection in order to ensure durable graft acceptance without immunosuppression. An important step in addressing this need is to strengthen our understanding of transplant immune tolerance mechanisms for both graft rejection and autoimmune rejection. Engineering of functional human pancreatic islets that can avoid attacks from host immune cells would provide an alternative safe resource for transplantation therapy. Human pluripotent stem cells (hPSCs) offer a potentially limitless supply of cells because of their self-renewal ability and pluripotency. Therefore, studying immune tolerance induction in hPSC-derived human pancreatic islets will directly contribute toward the goal of generating a functional cure for insulin-dependent diabetes. In this review, we will discuss the current progress in the immune protection of stem cell-derived islet cell therapy for treating diabetes.
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Affiliation(s)
- Meghan Tahbaz
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
| | - Eiji Yoshihara
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
- David Geffen School of Medicine at University of California, Los Angeles, CA, United States
- *Correspondence: Eiji Yoshihara,
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47
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Eskandari SK, Sulkaj I, Melo MB, Li N, Allos H, Alhaddad JB, Kollar B, Borges TJ, Eskandari AS, Zinter MA, Cai S, Assaker JP, Choi JY, Al Dulaijan BS, Mansouri A, Haik Y, Tannous BA, van Son WJ, Leuvenink HGD, Pomahac B, Riella LV, Tang L, Seelen MAJ, Irvine DJ, Azzi JR. Regulatory T cells engineered with TCR signaling-responsive IL-2 nanogels suppress alloimmunity in sites of antigen encounter. Sci Transl Med 2020; 12:eaaw4744. [PMID: 33177180 PMCID: PMC8519505 DOI: 10.1126/scitranslmed.aaw4744] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 06/03/2020] [Accepted: 09/03/2020] [Indexed: 07/30/2023]
Abstract
Adoptive cell transfer of ex vivo expanded regulatory T cells (Tregs) has shown immense potential in animal models of auto- and alloimmunity. However, the effective translation of such Treg therapies to the clinic has been slow. Because Treg homeostasis is known to require continuous T cell receptor (TCR) ligation and exogenous interleukin-2 (IL-2), some investigators have explored the use of low-dose IL-2 injections to increase endogenous Treg responses. Systemic IL-2 immunotherapy, however, can also lead to the activation of cytotoxic T lymphocytes and natural killer cells, causing adverse therapeutic outcomes. Here, we describe a drug delivery platform, which can be engineered to autostimulate Tregs with IL-2 in response to TCR-dependent activation, and thus activate these cells in sites of antigen encounter. To this end, protein nanogels (NGs) were synthesized with cleavable bis(N-hydroxysuccinimide) cross-linkers and IL-2/Fc fusion (IL-2) proteins to form particles that release IL-2 under reducing conditions, as found at the surface of T cells receiving stimulation through the TCR. Tregs surface-conjugated with IL-2 NGs were found to have preferential, allograft-protective effects relative to unmodified Tregs or Tregs stimulated with systemic IL-2. We demonstrate that murine and human NG-modified Tregs carrying an IL-2 cargo perform better than conventional Tregs in suppressing alloimmunity in murine and humanized mouse allotransplantation models. In all, the technology presented in this study has the potential to improve Treg transfer therapy by enabling the regulated spatiotemporal provision of IL-2 to antigen-primed Tregs.
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Affiliation(s)
- Siawosh K Eskandari
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Division of Nephrology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, Netherlands
| | - Ina Sulkaj
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Mariane B Melo
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Na Li
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Hazim Allos
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Juliano B Alhaddad
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Branislav Kollar
- Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Thiago J Borges
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Arach S Eskandari
- Department of Electrical Engineering, Delft University of Technology, 2628 CD Delft, Netherlands
| | - Max A Zinter
- Experimental Therapeutics and Molecular Imaging Unit, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
| | - Songjie Cai
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jean Pierre Assaker
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - John Y Choi
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Basmah S Al Dulaijan
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Amr Mansouri
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yousef Haik
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Bakhos A Tannous
- Experimental Therapeutics and Molecular Imaging Unit, Department of Neurology, Neuro-Oncology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
| | - Willem J van Son
- Division of Nephrology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, Netherlands
| | - Henri G D Leuvenink
- Department of Surgery, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, Netherlands
| | - Bohdan Pomahac
- Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Leonardo V Riella
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Li Tang
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
- Institute of Materials Science and Engineering, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Marc A J Seelen
- Division of Nephrology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, Netherlands
| | - Darrell J Irvine
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - Jamil R Azzi
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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48
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Wang K, Fu W. Transcriptional regulation of Treg homeostasis and functional specification. Cell Mol Life Sci 2020; 77:4269-4287. [PMID: 32350553 PMCID: PMC7606275 DOI: 10.1007/s00018-020-03534-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 04/19/2020] [Accepted: 04/20/2020] [Indexed: 12/15/2022]
Abstract
CD4+Foxp3+ regulatory T (Treg) cells are key players in keeping excessive inflammation in check. Mounting evidence has shown that Treg cells exert much more diverse functions in both immunological and non-immunological processes. The development, maintenance and functional specification of Treg cells are regulated by multilayered factors, including antigens and TCR signaling, cytokines, epigenetic modifiers and transcription factors (TFs). In the review, we will focus on TFs by summarizing their unique and redundant roles in Treg cells under physiological and pathophysiological conditions. We will also discuss the recent advances of Treg trajectories between lymphoid organs and non-lymphoid tissues. This review will provide an updated view of the newly identified TFs and new functions of known TFs in Treg biology.
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Affiliation(s)
- Ke Wang
- Pediatric Diabetes Research Center, Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Wenxian Fu
- Pediatric Diabetes Research Center, Department of Pediatrics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
- Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
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49
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Abstract
Over the last decade, there has been a considerable progress in the development of cell therapy products for the treatment of liver diseases. The quest to generate well-defined homogenous cell populations with defined mechanism(s) of action has enabled the progression from use of autologous bone marrow stem cells comprising of heterogeneous cell populations to allogeneic cell types such as monocyte-derived macrophages, regulatory T cells, mesenchymal stromal cells, macrophages, etc. There is growing evidence regarding the multiple molecular mechanisms pivotal to various therapeutic effects and hence, careful selection of cell therapy product for the desired putative effects is crucial. In this review, we have presented an overview of the cell therapies that have been developed thus far, with preclinical and clinical evidence for their use in liver disease. Limitations associated with these therapies have also been discussed. Despite the advances made, there remain multiple challenges to overcome before cell therapies can be considered as viable treatment options, and these include larger scale clinical trials, scalable production of cells according to good manufacturing practice standards, pathways for delivery of cell therapy within hospital environments, and costs associated with the production.
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Affiliation(s)
- Sheeba Khan
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Reenam S Khan
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Philip N Newsome
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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50
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Wang P, Jiang Z, Wang C, Liu X, Li H, Xu D, Zhong L. Immune Tolerance Induction Using Cell-Based Strategies in Liver Transplantation: Clinical Perspectives. Front Immunol 2020; 11:1723. [PMID: 33013824 PMCID: PMC7461870 DOI: 10.3389/fimmu.2020.01723] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 06/29/2020] [Indexed: 12/14/2022] Open
Abstract
Liver transplantation (LT) has become the best chance and a routine practice for patients with end-stage liver disease and small hepatocellular carcinoma. However, life-long immunosuppressive regimens could lead to many post-LT complications, including cancer recurrence, infections, dysmetabolic syndrome, and renal injury. Impeccable management of immunosuppressive regimens is indispensable to ensure the best long-term prognosis for LT recipients. This is challenging for these patients, who probably have a post-LT graft survival of more than 10 or even 20 years. Approximately 20% of patients after LT could develop spontaneous operational tolerance. They could maintain normal graft function and histology without any immunosuppressive regimens. Operational tolerance after transplantation has been an attractive and ultimate goal in transplant immunology. The liver, as an immunoregulatory organ, generates an immune hyporesponsive microenvironment under physiological conditions. In this regard, LT recipients may be ideal candidates for studies focusing on operative tolerance. Cell-based strategies are one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory T cells, regulatory dendritic cells, regulatory macrophages, regulatory B cells, and mesenchymal stromal cells. The safety and the efficacy of many cell products have been evaluated by prospective clinical trials. In this review, we will summarize the latest perspectives on the clinical application of cell-based strategies in LT and will address a number of concerns and future directions regarding these cell products.
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Affiliation(s)
- Pusen Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhongyi Jiang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chunguang Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueni Liu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dingyin Xu
- Department of Hepatobiliary Surgery, Ruian People's Hospital, Ruian, China
| | - Lin Zhong
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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