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1
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Liu D, Yao H, Ferrer IR, Ford ML. Differential induction of donor-reactive Foxp3 + regulatory T cell via blockade of CD154 vs CD40. Am J Transplant 2024; 24:1369-1381. [PMID: 38552961 PMCID: PMC11305915 DOI: 10.1016/j.ajt.2024.03.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 03/21/2024] [Accepted: 03/22/2024] [Indexed: 04/30/2024]
Abstract
Recently published studies in both murine models and a meta-analysis of non-human primate renal transplant studies showed that anti-CD154 reagents conferred a significant survival advantage over CD40 blockers in both animal models and across multiple organs. Here we sought to compare the induction of donor-reactive forkhead box P3+-induced regulatory T cells (Foxp3+ iTreg) in mice treated with anti-CD154 versus anti-CD40 monoclonal antibodies (mAbs). Results indicated that while treatment with anti-CD154 mAb resulted in a significant increase in the frequency of donor-reactive CD4+ Foxp3+ iTreg following transplantation, treatment with anti-CD40 or Cd40 deficiency failed to recapitulate this result. Because we recently identified CD11b as an alternate receptor for CD154 during alloimmunity, we interrogated the role of CD154:CD11b interactions in the generation of Foxp3+ iTreg and found that blockade of CD11b in Cd40-/- recipients resulted in increased donor-reactive Foxp3+ iTreg as compared with CD40 deficiency alone. Mechanistically, CD154:CD11b inhibition decreased interleukin (IL)-1β from CD11b+ and CD11c+ dendritic cells, and blockade of IL-1β synergized with CD40 deficiency to promote Foxp3+ iTreg induction and prolong allograft survival. Taken together, these data provide a mechanistic basis for the observed inferiority of anti-CD40 blockers as compared with anti-CD154 mAb and illuminate an IL-1β-dependent mechanism by which CD154:CD11b interactions prevent the generation of donor-reactive Foxp3+ iTreg during transplantation.
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Affiliation(s)
- Danya Liu
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, Georgia, USA
| | - Hongmin Yao
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, Georgia, USA
| | - Ivana R Ferrer
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, Georgia, USA
| | - Mandy L Ford
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, Georgia, USA.
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2
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Iglesias M, Bibicheff D, Komin A, Chicco M, Guinn S, Foley B, Raimondi G. T cell responsiveness to IL-10 defines the immunomodulatory effect of costimulation blockade via anti-CD154 and impacts transplant survival. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.12.598652. [PMID: 38915537 PMCID: PMC11195256 DOI: 10.1101/2024.06.12.598652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Costimulation blockade (CoB)-based immunotherapy is a promising alternative to immunosuppression for transplant recipients; however, the current limited understanding of the factors that impact its efficacy restrains its clinical applicability. In this context, pro- and anti-inflammatory cytokines are being recognized as having an impact on T cell activation beyond effector differentiation. This study aims at elucidating the impact of direct IL-10 signaling in T cells on CoB outcomes. We used a full-mismatch skin transplantation model where recipients had a T cell-restricted expression of a dominant negative IL-10 receptor (10R-DN), alongside anti-CD154 as CoB therapy. Unlike wild-type recipients, 10R-DN mice failed to benefit from CoB. This accelerated graft rejection correlated with increased accumulation of T cells producing TNF-α, IFN-γ, and IL-17. In vitro experiments indicated that while lack of IL-10 signaling did not change the ability of anti-CD154 to modulate alloreactive T cell proliferation, the absence of this pathway heightened TH1 effector cell differentiation. Furthermore, deficiency of IL-10 signaling in T cells impaired Treg induction, a hallmark of anti-CD154 therapy. Overall, these findings unveil an important and novel role of IL-10 signaling in T cells that defines the success of CoB therapies and identifies a target pathway for obtaining robust immunoregulation.
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Affiliation(s)
- Marcos Iglesias
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Darrel Bibicheff
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alexander Komin
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maria Chicco
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Samantha Guinn
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Brendan Foley
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Giorgio Raimondi
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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3
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Miura S, Habibabady ZA, Pollok F, Ma M, Rosales IA, Kinoshita K, Pratts S, McGrath G, Chaban R, Fogarty S, Meibohm B, Daugherty B, Lederman S, Pierson RN. TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate cardiac allograft survival. Am J Transplant 2023; 23:1182-1193. [PMID: 37030662 PMCID: PMC10524282 DOI: 10.1016/j.ajt.2023.03.025] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/16/2023] [Accepted: 03/29/2023] [Indexed: 04/10/2023]
Abstract
Blockade of the CD40/CD154 T cell costimulation pathway is a promising approach to supplement or replace current clinical immunosuppression in solid organ transplantation. We evaluated the tolerability and activity of a novel humanized anti-CD154 monoclonal antibody, TNX-1500 (TNX), in a nonhuman primate heterotopic cardiac allogeneic (allo) transplant model. TNX-1500 contains a rupluzimab fragment antigen-binding region and an immunoglobin G4 crystallizable fragment region engineered to reduce binding to the crystallizable fragment gamma receptor IIa and associated risks of thrombosis. Recipients were treated for 6 months with standard-dose TNX (sTNX) monotherapy, low-dose TNX monotherapy (loTNX), or loTNX with mycophenolate mofetil (MMF) (loTNX + MMF). Results were compared with historical data using chimeric humanized 5c8 monotherapy dosed as for loTNX but discontinued at 3 months. Median survival time was similar for humanized 5c8 and both loTNX groups, but significantly longer with sTNX (>265 days) than with loTNX (99 days) or loTNX + MMF (88 days) (P < 0.05 for both comparisons against sTNX). Standard-dose TNX prevented antidonor alloantibody elaboration, inhibited chronic rejection, and was associated with a significantly reduced effector T cells/regulatory T cells ratio relative to loTNX with MMF. No thrombotic complications were observed. This study demonstrated that TNX was well tolerated, prolongs allograft survival, and prevents alloantibody production and cardiac allograft vasculopathy in a stringent preclinical nonhuman primate heart allotransplant model.
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Affiliation(s)
- Shuhei Miura
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Cardiovascular Surgery, Sapporo Medical University, Sapporo, Japan; Department of Cardiovascular Surgery, Teine Keijinkai Hospital, Sapporo, Japan.
| | - Zahra A Habibabady
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Franziska Pollok
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Anesthesiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Madelyn Ma
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ivy A Rosales
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Kohei Kinoshita
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Shannon Pratts
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Gannon McGrath
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ryan Chaban
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | | | - Bernd Meibohm
- College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | | | | | - Richard N Pierson
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
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4
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Singh AK, Goerlich CE, Zhang T, Lewis BG, Hershfeld A, Mohiuddin MM. CD40-CD40L Blockade: Update on Novel Investigational Therapeutics for Transplantation. Transplantation 2023; 107:1472-1481. [PMID: 36584382 PMCID: PMC10287837 DOI: 10.1097/tp.0000000000004469] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Effective immune responses require antigen presentation by major histocompatibility complexes with cognate T-cell receptor and antigen-independent costimulatory signaling for T-cell activation, proliferation, and differentiation. Among several costimulatory signals, CD40-CD40L is of special interest to the transplantation community because it plays a vital role in controlling or regulating humoral and cellular immunity. Blockade of this pathway has demonstrated inhibition of donor-reactive T-cell responses and prolonged the survival of transplanted organs. Several anti-CD154 and anti-CD40 antibodies have been used in the transplantation model and demonstrated the potential of extending allograft and xenograft rejection-free survival. The wide use of anti-CD154 antibodies was hampered because of thromboembolic complications in transplant recipients. These antibodies have been modified to overcome the thromboembolic complications by altering the antibody binding fragment (Fab) and Fc (fragment, crystallizable) receptor region for therapeutic purposes. Here, we review recent preclinical advances to target the CD40-CD40L pair in transplantation.
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Affiliation(s)
| | | | - Tianshu Zhang
- University of Maryland School of Medicine, Baltimore, MD
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5
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Maenaka A, Kinoshita K, Hara H, Cooper DKC. The case for the therapeutic use of mechanistic/mammalian target of rapamycin (mTOR) inhibitors in xenotransplantation. Xenotransplantation 2023; 30:e12802. [PMID: 37029499 PMCID: PMC11286223 DOI: 10.1111/xen.12802] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 03/23/2023] [Indexed: 04/09/2023]
Abstract
The mechanistic/mammalian target of rapamycin (mTOR) is one of the systems that are necessary to maintain cell homeostasis, such as survival, proliferation, and differentiation. mTOR inhibitors (mTOR-Is) are utilized as immunosuppressants and anti-cancer drugs. In organ allotransplantation, current regimens infrequently include an mTOR-I, which are positioned more commonly as alternative immunosuppressants. In clinical allotransplantation, long-term efficacy has been established, but there is a significant incidence of adverse events, for example, inhibition of wound healing, buccal ulceration, anemia, hyperglycemia, dyslipidemia, and thrombocytopenia, some of which are dose-dependent. mTOR-Is have properties that may be especially beneficial in xenotransplantation. These include suppression of T cell proliferation, increases in the number of T regulatory cells, inhibition of pig graft growth, and anti-inflammatory, anti-viral, and anti-cancer effects. We here review the potential benefits and risks of mTOR-Is in xenotransplantation and suggest that the benefits exceed the adverse effects.
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Affiliation(s)
- Akihiro Maenaka
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Kohei Kinoshita
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Hidetaka Hara
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, Yunnan, China
| | - David K. C. Cooper
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
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6
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Socié G, Kean LS, Zeiser R, Blazar BR. Insights from integrating clinical and preclinical studies advance understanding of graft-versus-host disease. J Clin Invest 2021; 131:149296. [PMID: 34101618 PMCID: PMC8203454 DOI: 10.1172/jci149296] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
As a result of impressive increases in our knowledge of rodent and human immunology, the understanding of the pathophysiologic mechanisms underlying graft-versus-host disease (GVHD) has dramatically improved in the past 15 years. Despite improved knowledge, translation to clinical care has not proceeded rapidly, and results from experimental models have been inconsistent in their ability to predict the clinical utility of new therapeutic agents. In parallel, new tools in immunology have allowed in-depth analyses of the human system and have recently been applied in the field of clinical GVHD. Notwithstanding these advances, there is a relative paucity of mechanistic insights into human translational research, and this remains an area of high unmet need. Here we review selected recent advances in both preclinical experimental transplantation and translational human studies, including new insights into human immunology, the microbiome, and regenerative medicine. We focus on the fact that both approaches can interactively improve our understanding of both acute and chronic GVHD biology and open the door to improved therapeutics and successes.
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Affiliation(s)
- Gérard Socié
- Hematology-Transplantation, Assistance Publique–Hôpitaux de Paris (APHP), Hospital Saint Louis, Paris, France
- INSERM UMR 976 (Team Insights) and University of Paris, Paris, France
| | - Leslie S. Kean
- Division of Pediatric Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Robert Zeiser
- Department of Medicine I, Faculty of Medicine, Medical Center–University of Freiburg, Freiburg, Germany
| | - Bruce R. Blazar
- Masonic Cancer Center and Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, Minnesota, USA
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7
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Ding M, He Y, Zhang S, Guo W. Recent Advances in Costimulatory Blockade to Induce Immune Tolerance in Liver Transplantation. Front Immunol 2021; 12:537079. [PMID: 33732228 PMCID: PMC7959747 DOI: 10.3389/fimmu.2021.537079] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 01/12/2021] [Indexed: 01/25/2023] Open
Abstract
Liver transplantation is an effective therapy for end-stage liver disease. However, most postoperative patients must take immunosuppressive drugs to prevent organ rejection. Interestingly, some transplant recipients have normal liver function and do not experience organ rejection after the withdrawal of immunosuppressive agents. This phenomenon, called immune tolerance, is the ultimate goal in clinical transplantation. Costimulatory molecules play important roles in T cell-mediated immune responses and the maintenance of T cell tolerance. Blocking costimulatory pathways can alter T cell responses and prolong graft survival. Better understanding of the roles of costimulatory molecules has facilitated the use of costimulatory blockade to effectively induce immune tolerance in animal transplantation models. In this article, we review the state of the art in costimulatory pathway blockade for the induction of immune tolerance in transplantation and its potential application prospects for liver transplantation.
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Affiliation(s)
- Mingjie Ding
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
| | - Yuting He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
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8
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Zhao Y, Hu W, Chen P, Cao M, Zhang Y, Zeng C, Hara H, Cooper DKC, Mou L, Luan S, Gao H. Immunosuppressive and metabolic agents that influence allo‐ and xenograft survival by in vivo expansion of T regulatory cells. Xenotransplantation 2020; 27:e12640. [PMID: 32892428 DOI: 10.1111/xen.12640] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/06/2020] [Accepted: 08/17/2020] [Indexed: 12/23/2022]
Affiliation(s)
- Yanli Zhao
- Department of Nephrology Shenzhen Longhua District Central Hospital Affiliated Central Hospital of Shenzhen Longhua District Guangdong Medical University Shenzhen China
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center Institute of Translational Medicine Shenzhen University Health Science Center, Shenzhen University School of Medicine First Affiliated Hospital of Shenzhen UniversityShenzhen Second People’s Hospital Shenzhen China
- Department of Medical Laboratory Shenzhen Longhua District Central Hospital Affiliated Central Hospital of Shenzhen Longhua District Guangdong Medical University Shenzhen China
| | | | - Pengfei Chen
- Department of Nephrology Shenzhen Longhua District Central Hospital Affiliated Central Hospital of Shenzhen Longhua District Guangdong Medical University Shenzhen China
- Department of Medical Laboratory Shenzhen Longhua District Central Hospital Affiliated Central Hospital of Shenzhen Longhua District Guangdong Medical University Shenzhen China
| | - Mengtao Cao
- Department of Nephrology Shenzhen Longhua District Central Hospital Affiliated Central Hospital of Shenzhen Longhua District Guangdong Medical University Shenzhen China
- Department of Medical Laboratory Shenzhen Longhua District Central Hospital Affiliated Central Hospital of Shenzhen Longhua District Guangdong Medical University Shenzhen China
| | - Yingwei Zhang
- Department of Nephrology Shenzhen Longhua District Central Hospital Affiliated Central Hospital of Shenzhen Longhua District Guangdong Medical University Shenzhen China
| | - Changchun Zeng
- Department of Medical Laboratory Shenzhen Longhua District Central Hospital Affiliated Central Hospital of Shenzhen Longhua District Guangdong Medical University Shenzhen China
| | - Hidetaka Hara
- Xenotransplantation Program Department of Surgery University of Alabama at Birmingham Birmingham AL USA
| | - David K. C. Cooper
- Xenotransplantation Program Department of Surgery University of Alabama at Birmingham Birmingham AL USA
| | - Lisha Mou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center Institute of Translational Medicine Shenzhen University Health Science Center, Shenzhen University School of Medicine First Affiliated Hospital of Shenzhen UniversityShenzhen Second People’s Hospital Shenzhen China
| | - Shaodong Luan
- Department of Nephrology Shenzhen Longhua District Central Hospital Affiliated Central Hospital of Shenzhen Longhua District Guangdong Medical University Shenzhen China
| | - Hanchao Gao
- Department of Nephrology Shenzhen Longhua District Central Hospital Affiliated Central Hospital of Shenzhen Longhua District Guangdong Medical University Shenzhen China
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center Institute of Translational Medicine Shenzhen University Health Science Center, Shenzhen University School of Medicine First Affiliated Hospital of Shenzhen UniversityShenzhen Second People’s Hospital Shenzhen China
- Department of Medical Laboratory Shenzhen Longhua District Central Hospital Affiliated Central Hospital of Shenzhen Longhua District Guangdong Medical University Shenzhen China
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9
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Liu D, Ford ML. CD11b is a novel alternate receptor for CD154 during alloimmunity. Am J Transplant 2020; 20:2216-2225. [PMID: 32149455 PMCID: PMC7395865 DOI: 10.1111/ajt.15835] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/14/2020] [Accepted: 02/04/2020] [Indexed: 01/25/2023]
Abstract
Antagonism of the CD154/CD40 pathway is a highly effective means of inducing long-term graft survival in preclinical models. Using a fully allogeneic murine transplant model, we found that CD154 blockade was more effective in prolonging graft survival than was CD40 blockade, raising the possibility that CD154 binds a second receptor. To test this, we queried the impact of CD154 antagonism in the absence of CD40. Data indicated that anti-CD154 functioned to reduce graft-infiltrating CD8+ T cells in both WT and CD40-/- hosts. Because it has recently been reported that CD154 can ligate CD11b, we addressed the impact of blocking CD154-CD11b interactions during transplantation. We utilized a specific peptide antagonist that prevents CD154 binding of CD11b but has no effect on CD154-CD40 interactions. CD154:CD11b antagonism significantly increased the efficacy of anti-CD40 in prolonging allograft survival as compared to anti-CD40 plus control peptide. Mechanistically, CD154:CD11b antagonism functioned to reduce the frequency of graft-infiltrating CD8+ T cells and innate immune cells. These data therefore demonstrate that blocking CD154 interactions with both CD40 and CD11b is required for optimal inhibition of alloimmunity and provide an explanation for why CD40 blockers may be less efficacious than anti-CD154 reagents for the inhibition of allograft rejection.
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Affiliation(s)
- Danya Liu
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, Georgia
| | - Mandy L Ford
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, Georgia
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10
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Abstract
Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response and is not targeted with the conventional immunosuppressive therapy after kidney transplantation. Costimulation blockade therapy with biologicals allows precise targeting of the immune response but without non-immune adverse events. Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success. Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients. In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection. The purpose of this review is to provide an overview of the costimulation blockade therapies that are currently in use or being developed for kidney transplant indications.
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11
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Yu S, Su C, Luo X. Impact of infection on transplantation tolerance. Immunol Rev 2019; 292:243-263. [PMID: 31538351 PMCID: PMC6961566 DOI: 10.1111/imr.12803] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 08/29/2019] [Accepted: 09/03/2019] [Indexed: 12/12/2022]
Abstract
Allograft tolerance is the ultimate goal of organ transplantation. Current strategies for tolerance induction mainly focus on inhibiting alloreactive T cells while promoting regulatory immune cells. Pathogenic infections may have direct impact on both effector and regulatory cell populations, therefore can alter host susceptibility to transplantation tolerance induction as well as impair the quality and stability of tolerance once induced. In this review, we will discuss existing data demonstrating the effect of infections on transplantation tolerance, with particular emphasis on the role of the stage of infection (acute, chronic, or latent) and the stage of tolerance (induction or maintenance) in this infection-tolerance interaction. While the deleterious effect of acute infection on tolerance is mainly driven by proinflammatory cytokines induced shortly after the infection, chronic infection may generate exhausted T cells that could in fact facilitate transplantation tolerance. In addition to pathogenic infections, commensal intestinal microbiota also has numerous significant immunomodulatory effects that can shape the host alloimmunity following transplantation. A comprehensive understanding of these mechanisms is crucial for the development of therapeutic strategies for robustly inducing and stably maintaining transplantation tolerance while preserving host anti-pathogen immunity in clinically relevant scenarios.
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Affiliation(s)
- Shuangjin Yu
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, United States
- Division of Organ transplantation, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Chang Su
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, United States
| | - Xunrong Luo
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, United States
- Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, United States
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12
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Kim SC, Mathews DV, Breeden CP, Higginbotham LB, Ladowski J, Martens G, Stephenson A, Farris AB, Strobert EA, Jenkins J, Walters EM, Larsen CP, Tector M, Tector AJ, Adams AB. Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion. Am J Transplant 2019; 19:2174-2185. [PMID: 30821922 PMCID: PMC6658347 DOI: 10.1111/ajt.15329] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 01/22/2019] [Accepted: 02/04/2019] [Indexed: 01/25/2023]
Abstract
The shortage of available organs remains the greatest barrier to expanding access to transplant. Despite advances in genetic editing and immunosuppression, survival in experimental models of kidney xenotransplant has generally been limited to <100 days. We found that pretransplant selection of recipients with low titers of anti-pig antibodies significantly improved survival in a pig-to-rhesus macaque kidney transplant model (6 days vs median survival time 235 days). Immunosuppression included transient pan-T cell depletion and an anti-CD154-based maintenance regimen. Selective depletion of CD4+ T cells but not CD8+ T cells resulted in long-term survival (median survival time >400 days vs 6 days). These studies suggested that CD4+ T cells may have a more prominent role in xenograft rejection compared with CD8+ T cells. Although animals that received selective depletion of CD8+ T cells showed signs of early cellular rejection (marked CD4+ infiltrates), animals receiving selective CD4+ depletion exhibited normal biopsy results until late, when signs of chronic antibody rejection were present. In vitro study results suggested that rhesus CD4+ T cells required the presence of SLA class II to mount an effective proliferative response. The combination of low pretransplant anti-pig antibody and CD4 depletion resulted in consistent, long-term xenograft survival.
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Affiliation(s)
- SC Kim
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, Georgia
| | - DV Mathews
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, Georgia
| | - CP Breeden
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, Georgia
| | - LB Higginbotham
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, Georgia
| | - J Ladowski
- National Swine Resource and Research Center, University of Missouri, Columbia, Missouri
| | - G Martens
- National Swine Resource and Research Center, University of Missouri, Columbia, Missouri
| | - A Stephenson
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, Georgia
| | - AB Farris
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, Georgia
| | - EA Strobert
- Yerkes National Primate Research Center, School of Medicine, Emory University, Atlanta, Georgia
| | - J Jenkins
- Yerkes National Primate Research Center, School of Medicine, Emory University, Atlanta, Georgia
| | - EM Walters
- National Swine Resource and Research Center, University of Missouri, Columbia, Missouri
| | - CP Larsen
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, Georgia,Yerkes National Primate Research Center, School of Medicine, Emory University, Atlanta, Georgia
| | - M Tector
- Comprehensive Transplant Institute, University of Alabama Birmingham School of Medicine, Birmingham, Alabama
| | - AJ Tector
- Comprehensive Transplant Institute, University of Alabama Birmingham School of Medicine, Birmingham, Alabama
| | - AB Adams
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, Georgia,Yerkes National Primate Research Center, School of Medicine, Emory University, Atlanta, Georgia
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13
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14
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Abstract
β cell replacement with either pancreas or islet transplantation has progressed immensely over the last decades with current 1- and 5-year insulin independence rates of approximately 85% and 50%, respectively. Recent advances are largely attributed to improvements in immunosuppressive regimen, donor selection, and surgical technique. However, both strategies are compromised by a scarce donor source. Xenotransplantation offers a potential solution by providing a theoretically unlimited supply of islets, but clinical application has been limited by concerns for a potent immune response against xenogeneic tissue. β cell clusters derived from embryonic or induced pluripotent stem cells represent another promising unlimited source of insulin producing cells, but clinical application is pending further advances in the function of the β cell like clusters. Exciting developments and rapid progress in all areas of β cell replacement prompted a lively debate by members of the young investigator committee of the International Pancreas and Islet Transplant Association at the 15th International Pancreas and Islet Transplant Association Congress in Melbourne and at the 26th international congress of The Transplant Society in Hong Kong. This international group of young investigators debated which modality of β cell replacement would predominate the landscape in 10 years, and their arguments are summarized here.
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15
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Miller ML, McIntosh CM, Williams JB, Wang Y, Hollinger MK, Isaad NJ, Moon JJ, Gajewski TF, Chong AS, Alegre ML. Distinct Graft-Specific TCR Avidity Profiles during Acute Rejection and Tolerance. Cell Rep 2018; 24:2112-2126. [PMID: 30134172 PMCID: PMC6142813 DOI: 10.1016/j.celrep.2018.07.067] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 06/19/2018] [Accepted: 07/18/2018] [Indexed: 11/17/2022] Open
Abstract
Mechanisms implicated in robust transplantation tolerance at the cellular level can be broadly categorized into those that inhibit alloreactive T cells intrinsically (clonal deletion and dysfunction) or extrinsically through regulation. Here, we investigated whether additional population-level mechanisms control T cells by examining whether therapeutically induced peripheral transplantation tolerance could influence T cell populations' avidity for alloantigens. Whereas T cells with high avidity preferentially accumulated during acute rejection of allografts, the alloreactive T cells in tolerant recipients retained a low-avidity profile, comparable to naive mice despite evidence of activation. These contrasting avidity profiles upon productive versus tolerogenic stimulation were durable and persisted upon alloantigen re-encounter in the absence of any immunosuppression. Thus, peripheral transplantation tolerance involves control of alloreactive T cells at the population level, in addition to the individual cell level. Controlling expansion or eliminating high-affinity, donor-specific T cells long term may be desirable to achieve robust transplantation tolerance in the clinic.
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Affiliation(s)
- Michelle L Miller
- Department of Medicine, Section of Rheumatology, The University of Chicago, Chicago, IL 60637, USA
| | - Christine M McIntosh
- Department of Medicine, Section of Rheumatology, The University of Chicago, Chicago, IL 60637, USA
| | - Jason B Williams
- Department of Pathology, The University of Chicago, Chicago, IL 60637, USA
| | - Ying Wang
- Department of Medicine, Section of Rheumatology, The University of Chicago, Chicago, IL 60637, USA
| | - Maile K Hollinger
- Department of Medicine, Section of Rheumatology, The University of Chicago, Chicago, IL 60637, USA
| | - Noel J Isaad
- Department of Medicine, Section of Rheumatology, The University of Chicago, Chicago, IL 60637, USA
| | - James J Moon
- Center for Immunology and Inflammatory Diseases and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Medical School, Charlestown, MA 02129, USA
| | - Thomas F Gajewski
- Department of Pathology, The University of Chicago, Chicago, IL 60637, USA
| | - Anita S Chong
- Department of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL 60637, USA
| | - Maria-Luisa Alegre
- Department of Medicine, Section of Rheumatology, The University of Chicago, Chicago, IL 60637, USA.
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16
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Espinosa JR, Mou D, Adams BW, DiBernardo LR, MacDonald AL, McRae M, Miller AN, Song M, Stempora LL, Wang J, Iwakoshi NN, Kirk AD. T Cell Repertoire Maturation Induced by Persistent and Latent Viral Infection Is Insufficient to Induce Costimulation Blockade Resistant Organ Allograft Rejection in Mice. Front Immunol 2018; 9:1371. [PMID: 29963060 PMCID: PMC6013589 DOI: 10.3389/fimmu.2018.01371] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 06/01/2018] [Indexed: 12/22/2022] Open
Abstract
CD28:CD80/86 pathway costimulation blockade (CoB) with the CD80/86-specific fusion protein CTLA4-Ig prevents T cell-mediated allograft rejection in mice. However, in humans, transplantation with CoB has been hampered by CoB-resistant rejection (CoBRR). CoBRR has been attributed in part to pathogen-driven T cell repertoire maturation and resultant heterologous alloreactive memory. This has been demonstrated experimentally in mice. However, prior murine models have used viral pathogens, CoB regimens, graft types, and/or antigen systems atypically encountered clinically. We therefore sought to explore whether CoBRR would emerge in a model of virus-induced memory differentiation designed to more closely mimic clinical conditions. Specifically, we examined mouse homologs of clinically prevalent viruses including murine polyomavirus, cytomegalovirus, and gammaherpesvirus 68 in the presence of clinically relevant maintenance CoB regimens using a fully MHC-mismatched, vascularized allograft model. Infected mice developed a significant, sustained increase in effector memory T cells consistent with that seen in humans, but neither developed heterologous alloreactivity nor rejected primarily vascularized heterotopic heart transplants at an increased rate compared with uninfected mice. These results indicate that memory acquisition alone is insufficient to provoke CoBRR and suggest that knowledge of prior latent or persistent viral infection may have limited utility in anticipating heterologous CoB-resistant alloimmunity.
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Affiliation(s)
- Jaclyn R Espinosa
- Department of Surgery, Emory University, Atlanta, GA, United States.,Department of Surgery, Duke University, Durham, NC, United States
| | - Danny Mou
- Department of Surgery, Emory University, Atlanta, GA, United States
| | - Bartley W Adams
- Department of Surgery, Duke University, Durham, NC, United States
| | | | | | - MacKenzie McRae
- Department of Surgery, Duke University, Durham, NC, United States
| | - Allison N Miller
- Department of Surgery, Duke University, Durham, NC, United States
| | - Mingqing Song
- Department of Surgery, Duke University, Durham, NC, United States
| | - Linda L Stempora
- Department of Surgery, Duke University, Durham, NC, United States
| | - Jun Wang
- Department of Surgery, Duke University, Durham, NC, United States
| | - Neal N Iwakoshi
- Department of Surgery, Emory University, Atlanta, GA, United States
| | - Allan D Kirk
- Department of Surgery, Duke University, Durham, NC, United States
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17
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Singh AK, Chan JL, Seavey CN, Corcoran PC, Hoyt RF, Lewis BGT, Thomas ML, Ayares DL, Horvath KA, Mohiuddin MM. CD4+CD25 Hi FoxP3+ regulatory T cells in long-term cardiac xenotransplantation. Xenotransplantation 2018; 25:e12379. [PMID: 29250828 DOI: 10.1111/xen.12379] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 10/12/2017] [Accepted: 11/24/2017] [Indexed: 01/02/2023]
Abstract
BACKGROUND CD4+CD25Hi FoxP3+ T (Treg) cells are a small subset of CD4+ T cells that have been shown to exhibit immunoregulatory function. Although the absolute number of Treg cells in peripheral blood lymphocytes (PBL) is very small, they play an important role in suppressing immune reactivity. Several studies have demonstrated that the number of Treg cells, rather than their intrinsic suppressive capacity, may contribute to determining the long-term fate of transplanted grafts. In this study, we analyzed Treg cells in PBL of long-term baboon recipients who have received genetically modified cardiac xenografts from pig donors. METHODS Heterotopic cardiac xenotransplantation was performed on baboons using hearts obtained from GTKO.hCD46 (n = 8) and GTKO.hCD46.TBM (n = 5) genetically modified pigs. Modified immunosuppression regimen included antithymocyte globulin (ATG), anti-CD20, mycophenolate mofetil (MMF), cobra venom factor (CVF), and costimulation blockade (anti-CD154/anti-CD40 monoclonal antibody). FACS analysis was performed on PBLs labeled with anti-human CD4, CD25, and FoxP3 monoclonal antibodies (mAb) to analyze the percentage of Treg cells in six baboons that survived longer than 2 months (range: 42-945 days) after receiving a pig cardiac xenograft. RESULTS Total WBC count was low due to immunosuppression in baboons who received cardiac xenograft from GTKO.hCD46 and GTKO.hCD46.hTBM donor pigs. However, absolute numbers of CD4+CD25Hi FoxP3 Treg cells in PBLs of long-term xenograft cardiac xenograft surviving baboon recipients were found to be increased (15.13 ± 1.50 vs 7.38 ± 2.92; P < .018) as compared to naïve or pre-transplant baboons. Xenograft rejection in these animals was correlated with decreased numbers of regulatory T cells. CONCLUSION Our results suggest that regulatory T (Treg) cells may contribute to preventing or delaying xenograft rejection by controlling the activation and expansion of donor-reactive T cells, thereby masking the antidonor immune response, leading to long-term survival of cardiac xenografts.
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Affiliation(s)
- Avneesh K Singh
- Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
- Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Joshua L Chan
- Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Caleb N Seavey
- Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Philip C Corcoran
- Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Robert F Hoyt
- Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Billeta G T Lewis
- Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA
- Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD, USA
| | - Marvin L Thomas
- Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD, USA
| | | | - Keith A Horvath
- Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Muhammad M Mohiuddin
- Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
- Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA
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18
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Henry KA, Kim DY, Kandalaft H, Lowden MJ, Yang Q, Schrag JD, Hussack G, MacKenzie CR, Tanha J. Stability-Diversity Tradeoffs Impose Fundamental Constraints on Selection of Synthetic Human V H/V L Single-Domain Antibodies from In Vitro Display Libraries. Front Immunol 2017; 8:1759. [PMID: 29375542 PMCID: PMC5763143 DOI: 10.3389/fimmu.2017.01759] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 11/27/2017] [Indexed: 11/18/2022] Open
Abstract
Human autonomous VH/VL single-domain antibodies (sdAbs) are attractive therapeutic molecules, but often suffer from suboptimal stability, solubility and affinity for cognate antigens. Most commonly, human sdAbs have been isolated from in vitro display libraries constructed via synthetic randomization of rearranged VH/VL domains. Here, we describe the design and characterization of three novel human VH/VL sdAb libraries through a process of: (i) exhaustive biophysical characterization of 20 potential VH/VL sdAb library scaffolds, including assessment of expression yield, aggregation resistance, thermostability and tolerance to complementarity-determining region (CDR) substitutions; (ii) in vitro randomization of the CDRs of three VH/VL sdAb scaffolds, with tailored amino acid representation designed to promote solubility and expressibility; and (iii) systematic benchmarking of the three VH/VL libraries by panning against five model antigens. We isolated ≥1 antigen-specific human sdAb against four of five targets (13 VHs and 7 VLs in total); these were predominantly monomeric, had antigen-binding affinities ranging from 5 nM to 12 µM (average: 2–3 µM), but had highly variable expression yields (range: 0.1–19 mg/L). Despite our efforts to identify the most stable VH/VL scaffolds, selection of antigen-specific binders from these libraries was unpredictable (overall success rate for all library-target screens: ~53%) with a high attrition rate of sdAbs exhibiting false positive binding by ELISA. By analyzing VH/VL sdAb library sequence composition following selection for monomeric antibody expression (binding to protein A/L followed by amplification in bacterial cells), we found that some VH/VL sdAbs had marked growth advantages over others, and that the amino acid composition of the CDRs of this set of sdAbs was dramatically restricted (bias toward Asp and His and away from aromatic and hydrophobic residues). Thus, CDR sequence clearly dramatically impacts the stability of human autonomous VH/VL immunoglobulin domain folds, and sequence-stability tradeoffs must be taken into account during the design of such libraries.
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Affiliation(s)
- Kevin A Henry
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada
| | - Dae Young Kim
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada
| | - Hiba Kandalaft
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada
| | - Michael J Lowden
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada
| | - Qingling Yang
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada
| | - Joseph D Schrag
- Human Health Therapeutics Research Centre, National Research Council Canada, Montréal, QC, Canada
| | - Greg Hussack
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada
| | - C Roger MacKenzie
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada.,School of Environmental Sciences, University of Guelph, Guelph, ON, Canada
| | - Jamshid Tanha
- Human Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, Canada.,School of Environmental Sciences, University of Guelph, Guelph, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
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19
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Chen J, Song Y, Bojadzic D, Tamayo-Garcia A, Landin AM, Blomberg BB, Buchwald P. Small-Molecule Inhibitors of the CD40-CD40L Costimulatory Protein-Protein Interaction. J Med Chem 2017; 60:8906-8922. [PMID: 29024591 PMCID: PMC5823691 DOI: 10.1021/acs.jmedchem.7b01154] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Costimulatory interactions are required for T cell activation and development of an effective immune response; hence, they are valuable therapeutic targets for immunomodulation. However, they, as all other protein-protein interactions, are difficult to target by small molecules. Here, we report the identification of novel small-molecule inhibitors of the CD40-CD40L interaction designed starting from the chemical space of organic dyes. For the most promising compounds such as DRI-C21045, activity (IC50) in the low micromolar range has been confirmed in cell assays including inhibition of CD40L-induced activation in NF-κB sensor cells, THP-1 myeloid cells, and primary human B cells as well as in murine allogeneic skin transplant and alloantigen-induced T cell expansion in draining lymph node experiments. Specificity versus other TNF-superfamily interactions (TNF-R1-TNF-α) and lack of cytotoxicity have also been confirmed at these concentrations. These novel compounds provide proof-of-principle evidence for the possibility of small-molecule inhibition of costimulatory protein-protein interactions, establish the structural requirements needed for efficient CD40-CD40L inhibition, and serve to guide the search for such immune therapeutics.
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Affiliation(s)
- Jinshui Chen
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Yun Song
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
- Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Damir Bojadzic
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Alejandro Tamayo-Garcia
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Ana Marie Landin
- Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Bonnie B. Blomberg
- Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
- Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
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20
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Young JS, Khiew SHW, Yang J, Vannier A, Yin D, Sciammas R, Alegre ML, Chong AS. Successful Treatment of T Cell-Mediated Acute Rejection with Delayed CTLA4-Ig in Mice. Front Immunol 2017; 8:1169. [PMID: 28970838 PMCID: PMC5609110 DOI: 10.3389/fimmu.2017.01169] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 09/04/2017] [Indexed: 12/25/2022] Open
Abstract
Clinical observations that kidney transplant recipients receiving belatacept who experienced T cell-mediated acute rejection can be successfully treated and subsequently maintained on belatacept-based immunosuppression suggest that belatacept is able to control memory T cells. We recently reported that treatment with CTLA4-Ig from day 6 posttransplantation successfully rescues allografts from acute rejection in a BALB/c to C57BL/6 heart transplant model, in part, by abolishing B cell germinal centers and reducing alloantibody titers. Here, we show that CTLA4-Ig is additionally able to inhibit established T cell responses independently of B cells. CTLA4-Ig inhibited the in vivo cytolytic activity of donor-specific CD8+ T cells, and the production of IFNγ by graft-infiltrating T cells. Delayed CTLA4-Ig treatment did not reduce the numbers of graft-infiltrating T cells nor prevented the accumulation of antigen-experienced donor-specific memory T cells in the spleen. Nevertheless, delayed CTLA4-Ig treatment successfully maintained long-term graft acceptance in the majority of recipients that had experienced a rejection crisis, and enabled the acceptance of secondary BALB/c heart grafts transplanted 30 days after the first transplantation. In summary, we conclude that delayed CTLA4-Ig treatment is able to partially halt ongoing T cell-mediated acute rejection. These findings extend the functional efficacy of CTLA4-Ig therapy to effector T cells and provide an explanation for why CTLA4-Ig-based immunosuppression in the clinic successfully maintains long-term graft survival after T cell-mediated rejection.
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Affiliation(s)
- James S Young
- Department of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United States
| | - Stella H-W Khiew
- Department of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United States
| | - Jinghui Yang
- Department of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United States.,Department of Organ Transplantation, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Augustin Vannier
- Department of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United States
| | - Dengping Yin
- Department of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United States
| | - Roger Sciammas
- Center for Comparative Medicine, University of California, Davis, Davis, CA, United States
| | - Maria-Luisa Alegre
- Department of Medicine, Section of Rheumatology, The University of Chicago, Chicago, IL, United States
| | - Anita S Chong
- Department of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United States
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21
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Crepeau RL, Ford ML. Challenges and opportunities in targeting the CD28/CTLA-4 pathway in transplantation and autoimmunity. Expert Opin Biol Ther 2017; 17:1001-1012. [PMID: 28525959 DOI: 10.1080/14712598.2017.1333595] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. Areas covered: This review discusses past, current and future biological therapies that have been utilized to block the CD28/CTLA-4 cosignaling pathway in the settings of autoimmunity and transplantation, as well the challenges facing successful implementation of these therapies. Expert opinion: The development of CD28 blockers Abatacept and Belatacept provided a more targeted therapy approach for transplant rejection and autoimmune disease relative to calcineurin inhibitors and anti-proliferatives, but overall efficacy may be limited due to their collateral effect of simultaneously blocking CTLA-4 coinhibitory signals. As such, current investigations into the potential of selective CD28 blockade to block the costimulatory potential of CD28 while exploiting the coinhibitory effects of CTLA-4 are promising. However, as selective CD28 blockade inhibits the activity of both effector and regulatory T cells, an important goal for the future is the design of therapies that will maximize the attenuation of effector responses while preserving the suppressive function of T regulatory cells.
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Affiliation(s)
- Rebecca L Crepeau
- a Emory Transplant Center and Department of Surgery , Emory University , Atlanta , GA , USA
| | - Mandy L Ford
- a Emory Transplant Center and Department of Surgery , Emory University , Atlanta , GA , USA
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22
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Kim SC, Wakwe W, Higginbotham LB, Mathews DV, Breeden CP, Stephenson AC, Jenkins J, Strobert E, Price K, Price L, Kuhn R, Wang H, Yamniuk A, Suchard S, Farris AB, Pearson TC, Larsen CP, Ford ML, Suri A, Nadler S, Adams AB. Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection. Am J Transplant 2017; 17:1182-1192. [PMID: 28097811 PMCID: PMC5409881 DOI: 10.1111/ajt.14197] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 12/28/2016] [Accepted: 12/29/2016] [Indexed: 01/25/2023]
Abstract
The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.
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Affiliation(s)
- Steven C Kim
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Walter Wakwe
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Laura B Higginbotham
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - David V Mathews
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Cynthia P Breeden
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Allison C Stephenson
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Joe Jenkins
- Yerkes National Primate Research Center, School of Medicine, Emory University, Atlanta, GA, USA
| | - Elizabeth Strobert
- Yerkes National Primate Research Center, School of Medicine, Emory University, Atlanta, GA, USA
| | - Karen Price
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Laura Price
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Robert Kuhn
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Haiqing Wang
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Aaron Yamniuk
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Suzanne Suchard
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Alton B Farris
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Thomas C Pearson
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Christian P Larsen
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Mandy L Ford
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Anish Suri
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Steven Nadler
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Andrew B Adams
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
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23
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Govender L, Wyss JC, Kumar R, Pascual M, Golshayan D. IL-2-Mediated In Vivo Expansion of Regulatory T Cells Combined with CD154-CD40 Co-Stimulation Blockade but Not CTLA-4 Ig Prolongs Allograft Survival in Naive and Sensitized Mice. Front Immunol 2017; 8:421. [PMID: 28484450 PMCID: PMC5399033 DOI: 10.3389/fimmu.2017.00421] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 03/24/2017] [Indexed: 01/03/2023] Open
Abstract
In recent years, regulatory T cells (Treg)-based immunotherapy has emerged as a promising strategy to promote operational tolerance after solid organ transplantation (SOT). However, a main hurdle for the therapeutic use of Treg in transplantation is their low frequency, particularly in non-lymphopenic hosts. We aimed to expand Treg directly in vivo and determine their efficacy in promoting donor-specific tolerance, using a stringent experimental model. Administration of the IL-2/JES6-1 immune complex at the time of transplantation resulted in significant expansion of donor-specific Treg, which suppressed alloreactive T cells. IL-2-mediated Treg expansion in combination with short-term CD154–CD40 co-stimulation blockade, but not CTLA-4 Ig or rapamycin, led to tolerance to MHC-mismatched skin grafts in non-lymphopenic mice, mainly by hindering alloreactive CD8+ effector T cells and the production of alloantibodies. Importantly, this treatment also allowed prolonged survival of allografts in the presence of either donor-specific or cross-reactive memory cells. However, late rejection occurred in sensitized hosts, partly mediated by activated B cells. Overall, these data illustrate the potential but also some important limitations of Treg-based therapy in clinical SOT as well as the importance of concomitant immunomodulatory strategies in particular in sensitized hosts.
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Affiliation(s)
- Lerisa Govender
- Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Jean-Christophe Wyss
- Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Rajesh Kumar
- Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Manuel Pascual
- Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Dela Golshayan
- Transplantation Centre and Transplantation Immunopathology Laboratory, Service of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
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Kean LS, Turka LA, Blazar BR. Advances in targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy. Immunol Rev 2017; 276:192-212. [PMID: 28258702 PMCID: PMC5338458 DOI: 10.1111/imr.12523] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In the past decade, the power of harnessing T-cell co-signaling pathways has become increasingly understood to have significant clinical importance. In cancer immunotherapy, the field has concentrated on two related modalities: First, targeting cancer antigens through highly activated chimeric antigen T cells (CAR-Ts) and second, re-animating endogenous quiescent T cells through checkpoint blockade. In each of these strategies, the therapeutic goal is to re-ignite T-cell immunity, in order to eradicate tumors. In transplantation, there is also great interest in targeting T-cell co-signaling, but with the opposite goal: in this field, we seek the Yin to cancer immunotherapy's Yang, and focus on manipulating T-cell co-signaling to induce tolerance rather than activation. In this review, we discuss the major T-cell signaling pathways that are being investigated for tolerance induction, detailing preclinical studies and the path to the clinic for many of these molecules. These include blockade of co-stimulation pathways and agonism of coinhibitory pathways, in order to achieve the delicate state of balance that is transplant tolerance: a state which guarantees lifelong transplant acceptance without ongoing immunosuppression, and with preservation of protective immune responses. In the context of the clinical translation of immune tolerance strategies, we discuss the significant challenge that is embodied by the fact that targeted pathway modulators may have opposing effects on tolerance based on their impact on effector vs regulatory T-cell biology. Achieving this delicate balance holds the key to the major challenge of transplantation: lifelong control of alloreactivity while maintaining an otherwise intact immune system.
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Affiliation(s)
- Leslie S Kean
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA
- The Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Laurence A Turka
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Immune Tolerance Network, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
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25
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Ansari AW, Khan MA, Schmidt RE, Broering DC. Harnessing the immunotherapeutic potential of T-lymphocyte co-signaling molecules in transplantation. Immunol Lett 2017; 183:8-16. [PMID: 28119073 DOI: 10.1016/j.imlet.2017.01.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 01/10/2017] [Accepted: 01/12/2017] [Indexed: 12/12/2022]
Abstract
Alloantigen-specific T-cell triggered immunopathological events are responsible for rapid allograft rejection. The co-signaling pathways orchestrated by co-stimulatory and co-inhibitory molecules are critical for optimal T-cell effector function. Therefore, selective blockade of pathways that control T-cell immunity may offer an attractive therapeutic strategy to manipulate cell mediated allogenic responses. For example, CD28, CTLA-4 and CD154 receptor blockade have proven beneficial in maintaining T-cell tolerance against transplanted organs in experimental animal models as well as in clinical trials. Conversely, induction of co-inhibitory molecules may result in suppressed effector function. There are several other potential molecules that are known to induce immune tolerance are currently under consideration for clinical studies. In this review, we provide a comprehensive and updated analysis of co-stimulatory and co-inhibitory molecules, their therapeutic potential to prevent graft rejection, and to further improve their long-term survival.
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Affiliation(s)
- Abdul W Ansari
- Organ Transplant Research Section, Department of Comparative Medicine, MBC03, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.
| | - Mohammad A Khan
- Organ Transplant Research Section, Department of Comparative Medicine, MBC03, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia
| | - Reinhold E Schmidt
- Department of Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg Str.1, D-30625 Hannover, Germany
| | - Dieter C Broering
- Organ Transplant Research Section, Department of Comparative Medicine, MBC03, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.
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26
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Schwarz C, Unger L, Mahr B, Aumayr K, Regele H, Farkas AM, Hock K, Pilat N, Wekerle T. The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses. Am J Transplant 2016; 16:3404-3415. [PMID: 27184870 DOI: 10.1111/ajt.13872] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 04/18/2016] [Accepted: 05/09/2016] [Indexed: 01/25/2023]
Abstract
B7.1/2-targeted costimulation blockade (CTLA4 immunoglobulin [CTLA4-Ig]) is available for immunosuppression after kidney transplantation, but its potentially detrimental impact on regulatory T cells (Tregs) is of concern. We investigated the effects of CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). CTLA4-Ig was injected chronically (on days 0, 4, 14, and 28 and every 4 weeks thereafter) in dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high dose (HD), 1.25 mg (≈50 mg/kg body weight); and very high dose (VHD), 6.25 mg (≈250 mg/kg body weight). Chronic CTLA4-Ig therapy showed dose-dependent efficacy, with the LD regimen prolonging graft survival and with the HD and VHD regimens leading to >95% long-term graft survival and preserved histology. CTLA4-Ig's effect was immunosuppressive rather than tolerogenic because treatment cessation after ≈3 mo led to rejection. FoxP3-positive Tregs were reduced in naïve mice to a similar degree, independent of the CTLA4-Ig dose, but recovered to normal values in heart recipients under chronic CTLA4-Ig therapy. Treg depletion (anti-CD25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA4-Ig therapy is impaired when Tregs are removed, whereas CTLA4-Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.
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Affiliation(s)
- C Schwarz
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - L Unger
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - B Mahr
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - K Aumayr
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - H Regele
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - A M Farkas
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - K Hock
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - N Pilat
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - T Wekerle
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
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27
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Young JS, Chen J, Miller ML, Vu V, Tian C, Moon JJ, Alegre ML, Sciammas R, Chong AS. Delayed Cytotoxic T Lymphocyte-Associated Protein 4-Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection. Am J Transplant 2016; 16:2312-23. [PMID: 26928966 PMCID: PMC4956497 DOI: 10.1111/ajt.13761] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 02/18/2016] [Accepted: 02/21/2016] [Indexed: 01/25/2023]
Abstract
Antibody-mediated rejection has emerged as the leading cause of late graft loss in kidney transplant recipients, and inhibition of donor-specific antibody production should lead to improved transplant outcomes. The fusion protein cytotoxic T lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) blocks T cell activation and consequently inhibits T-dependent B cell antibody production, and the current paradigm is that CTLA4-Ig is effective with naïve T cells and less so with activated or memory T cells. In this study, we used a mouse model of allosensitization to investigate the efficacy of continuous CTLA4-Ig treatment, initiated 7 or 14 days after sensitization, for inhibiting ongoing allospecific B cell responses. Delayed treatment with CTLA4-Ig collapsed the allospecific germinal center B cell response and inhibited alloantibody production. Using adoptively transferred T cell receptor transgenic T cells and a novel approach to track endogenous graft-specific T cells, we demonstrate that delayed CTLA4-Ig minimally inhibited graft-specific CD4(+) and T follicular helper responses. Remarkably, delaying CTLA4-Ig until day 6 after transplantation in a fully mismatched heart transplant model inhibited alloantibody production and prevented acute rejection, whereas transferred hyperimmune sera reversed the effects of delayed CTLA4-Ig. Collectively, our studies revealed the unexpected efficacy of CTLA4-Ig for inhibiting ongoing B cell responses even when the graft-specific T cell response was robustly established.
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Affiliation(s)
- James S. Young
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL
| | - Jianjun Chen
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL
| | - Michelle L. Miller
- Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL
| | - Vinh Vu
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL
| | - Changtai Tian
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL
| | - James J. Moon
- Center for Immunology and Inflammatory Diseases, and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital; and Harvard Medical School, Boston, MA
| | - Maria-Luisa Alegre
- Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL
| | - Roger Sciammas
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL
| | - Anita S. Chong
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL
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28
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Hotta K, Aoyama A, Oura T, Yamada Y, Tonsho M, Huh KH, Kawai K, Schoenfeld D, Allan JS, Madsen JC, Benichou G, Smith RN, Colvin RB, Sachs DH, Cosimi AB, Kawai T. Induced regulatory T cells in allograft tolerance via transient mixed chimerism. JCI Insight 2016; 1. [PMID: 27446989 DOI: 10.1172/jci.insight.86419] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Successful induction of allograft tolerance has been achieved in nonhuman primates (NHPs) and humans via induction of transient hematopoietic chimerism. Since allograft tolerance was achieved in these recipients without durable chimerism, peripheral mechanisms are postulated to play a major role. Here, we report our studies of T cell immunity in NHP recipients that achieved long-term tolerance versus those that rejected the allograft (AR). All kidney, heart, and lung transplant recipients underwent simultaneous or delayed donor bone marrow transplantation (DBMT) following conditioning with a nonmyeloablative regimen. After DBMT, mixed lymphocyte culture with CFSE consistently revealed donor-specific loss of CD8+ T cell responses in tolerant (TOL) recipients, while marked CD4+ T cell proliferation in response to donor antigens was found to persist. Interestingly, a significant proportion of the proliferated CD4+ cells were FOXP3+ in TOL recipients, but not in AR or naive NHPs. In TOL recipients, CD4+FOXP3+ cell proliferation against donor antigens was greater than that observed against third-party antigens. Finally, the expanded Tregs appeared to be induced Tregs (iTregs) that were converted from non-Tregs. These data provide support for the hypothesis that specific induction of iTregs by donor antigens is key to long-term allograft tolerance induced by transient mixed chimerism.
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Affiliation(s)
- Kiyohiko Hotta
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Akihiro Aoyama
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Tetsu Oura
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Yohei Yamada
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Makoto Tonsho
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Kyu Ha Huh
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Kento Kawai
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - David Schoenfeld
- Department of Biostatistics, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - James S Allan
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Joren C Madsen
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Gilles Benichou
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Rex-Neal Smith
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Robert B Colvin
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - David H Sachs
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - A Benedict Cosimi
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Tatsuo Kawai
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Abstract
PURPOSE OF REVIEW Transplantation tolerance, successful acceptance of an organ without the perils of immunosuppression, has been a central goal of transplant research. Many strategies to achieve this tolerance have been examined over the past three decades, culminating in several human trials of transplant tolerance. This progression from the 'benchtop to the clinic' has depended on the successful implementation of these tolerance strategies in nonhuman primates. This review will examine the described methods of transplant tolerance induction in nonhuman primates. RECENT FINDINGS Although costimulatory blockade and mixed chimerism have an established record of achieving transplant tolerance in nonhuman primates, some of the most innovative recent techniques of tolerance induction have relied on cellular transfer. This review will fully examine the role of regulatory T-cell transfer and the use of mesenchymal stem/stromal cells to promote tolerance of organ allografts in nonhuman primates. SUMMARY Use of translational nonhuman primate transplant models is a vital intermediate step to advance new approaches of transplant tolerance induction from the lab to the clinic. This review will explore numerous techniques of tolerance induction that have been piloted in primates, including depletional techniques, induction of mixed hematopoietic chimerism, costimulation blockade, and adoptive transfer of tolerogenic cell populations.
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30
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Vogel I, Verbinnen B, Van Gool S, Ceuppens JL. Regulatory T Cell-Dependent and -Independent Mechanisms of Immune Suppression by CD28/B7 and CD40/CD40L Costimulation Blockade. THE JOURNAL OF IMMUNOLOGY 2016; 197:533-40. [PMID: 27288533 DOI: 10.4049/jimmunol.1502039] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 05/10/2016] [Indexed: 02/04/2023]
Abstract
Blocking of costimulatory CD28/B7 and CD40/CD40L interactions is an experimental approach to immune suppression and tolerance induction. We previously reported that administration of a combination of CTLA-4Ig and MR1 (anti-CD40L mAb) for blockade of these interactions induces tolerance in a fully mismatched allogeneic splenocyte transfer model in mice. We now used this model to study whether regulatory T cells (Tregs) contribute to immune suppression and why both pathways have to be blocked simultaneously. Mice were injected with allogeneic splenocytes, CD4(+) T cells, or CD8(+) T cells and treated with MR1 mAb and different doses of CTLA-4Ig. The graft-versus-host reaction of CD4(+) T cells, but not of CD8(+) T cells, was inhibited by MR1. CTLA-4Ig was needed to cover CD8(+) T cells but had only a weak effect on CD4(+) T cells. Consequently, only the combination provided full protection when splenocytes were transferred. Importantly, MR1 and low-dose CTLA-4Ig treatment resulted in a relative increase in Tregs, and immune suppressive efficacy was abolished in the absence of Tregs. High-dose CTLA-4Ig treatment, in contrast, prevented Treg expansion and activity, and in combination with MR1 completely inhibited CD4(+) and CD8(+) T cell activation in a Treg-independent manner. In conclusion, MR1 and CTLA-4Ig act synergistically as they target different T cell populations. The contribution of Tregs to immune suppression by costimulation blockade depends on the concentration of CTLA-4Ig and thus on the degree of available CD28 costimulation.
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Affiliation(s)
- Isabel Vogel
- Laboratory of Clinical Immunology, KULeuven, University Hospital Gasthuisberg, 3000 Leuven, Belgium; and
| | - Bert Verbinnen
- Laboratory of Clinical Immunology, KULeuven, University Hospital Gasthuisberg, 3000 Leuven, Belgium; and
| | - Stefaan Van Gool
- Laboratory of Clinical Immunology, KULeuven, University Hospital Gasthuisberg, 3000 Leuven, Belgium; and Childhood Immunology, KULeuven, University Hospital Gasthuisberg, 3000 Leuven, Belgium
| | - Jan L Ceuppens
- Laboratory of Clinical Immunology, KULeuven, University Hospital Gasthuisberg, 3000 Leuven, Belgium; and
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Abstract
The ultimate outcome of alloreactivity versus tolerance following transplantation is potently influenced by the constellation of cosignaling molecules expressed by immune cells during priming with alloantigen, and the net sum of costimulatory and coinhibitory signals transmitted via ligation of these molecules. Intense investigation over the last two decades has yielded a detailed understanding of the kinetics, cellular distribution, and intracellular signaling networks of cosignaling molecules such as the CD28, TNF, and TIM families of receptors in alloimmunity. More recent work has better defined the cellular and molecular mechanisms by which engagement of cosignaling networks serve to either dampen or augment alloimmunity. These findings will likely aid in the rational development of novel immunomodulatory strategies to prolong graft survival and improve outcomes following transplantation.
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Affiliation(s)
- Mandy L Ford
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, GA 30322, USA.
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32
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Del Bello A, Marion O, Milongo D, Rostaing L, Kamar N. Belatacept prophylaxis against organ rejection in adult kidney-transplant recipients. Expert Rev Clin Pharmacol 2015; 9:215-27. [PMID: 26691282 DOI: 10.1586/17512433.2016.1112736] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
End-stage renal disease is a major health problem worldwide, with kidney transplantation being the treatment of choice. Calcineurin inhibitors are still the cornerstone of immunosuppressive therapy. However, they have well-known nephrotoxic affects and increase the risk of cardiovascular disease and cancer. In contrast, belatacept is a biological immunosuppressive agent that inhibits the T-cell co-stimulation. It is approved by the US Food and Drug Administration and the European Medicine Agency for use in adult kidney-transplant recipients to prevent acute rejection. Developmental studies show that belatacept is as efficient as calcineurin inhibitors at preventing acute rejection. In addition, kidney function is better and cardiovascular risk factors are reduced in patients given belatacept. Herein, the authors review the published evidence concerning the efficacy and safety of belatacept and discuss its potential specific indications.
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Affiliation(s)
- Arnaud Del Bello
- a Department of Nephrology and Organ Transplantation , CHU Rangueil , Toulouse , France.,b Faculte de Medecine , Université Paul Sabatier , Toulouse , France
| | - Olivier Marion
- a Department of Nephrology and Organ Transplantation , CHU Rangueil , Toulouse , France
| | - David Milongo
- a Department of Nephrology and Organ Transplantation , CHU Rangueil , Toulouse , France
| | - Lionel Rostaing
- a Department of Nephrology and Organ Transplantation , CHU Rangueil , Toulouse , France.,b Faculte de Medecine , Université Paul Sabatier , Toulouse , France.,c INSERM U1043, IFR-BMT, CHU Purpan , Toulouse , France
| | - Nassim Kamar
- a Department of Nephrology and Organ Transplantation , CHU Rangueil , Toulouse , France.,b Faculte de Medecine , Université Paul Sabatier , Toulouse , France.,c INSERM U1043, IFR-BMT, CHU Purpan , Toulouse , France
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33
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Aloui C, Sut C, Cognasse F, Granados V, Hassine M, Chakroun T, Garraud O, Laradi S. Development of a highly resolutive method, using a double quadruplex tetra-primer-ARMS-PCR coupled with capillary electrophoresis to study CD40LG polymorphisms. Mol Cell Probes 2015; 29:335-342. [PMID: 26577033 DOI: 10.1016/j.mcp.2015.11.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 11/06/2015] [Accepted: 11/06/2015] [Indexed: 12/18/2022]
Abstract
Polymorphisms in the CD40 ligand gene (CD40LG) are associated with various immunological disorders such as tumors, autoimmune and infectious diseases. The aim of this study was to develop a highly optimized double quadruplex tetra-primer amplification refractory mutation system PCR (double quadruplex T-ARMS-PCR) coupled with capillary electrophoresis to allow genotyping of eight relevant candidate CD40LG SNPs and to establish haplotypes. After conducting the double quadruplex T-ARMS-PCR, the genotypes obtained through agarose electrophoresis were compared with those obtained through capillary electrophoresis. This strategy was applied to analyze the genetic patterns of CD40LG in two distinct cohorts of blood donors (211 French and 274 Tunisian). The T-ARMS-PCR method was rapid, inexpensive, reproducible and reliable for SNP determination. Regarding the separation technique, capillary electrophoresis allows traceable and semi-automated analysis while agarose electrophoresis remains a cost-effective technique that does not require specialized or costly equipment. Using these methods, we identified significantly different genetic heterogeneity between the two investigated populations (p ≤ 0.0001) and we also extensively characterized their haplotypes. The obtained genotype distribution and the optimized quadruplex T-ARMS-PCR technique coupled with capillary electrophoresis provides valuable information for studying pathologic inflammation leading to various diseases in which CD40LG might be a candidate gene.
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Affiliation(s)
- Chaker Aloui
- GIMAP-EA3064, University of Lyon, Saint-Etienne, 42270 Saint-Priest-en-Jarez, France; French Blood Establishment, EFS Auvergne-Loire, 42023 Saint-Etienne, France
| | - Caroline Sut
- GIMAP-EA3064, University of Lyon, Saint-Etienne, 42270 Saint-Priest-en-Jarez, France; French Blood Establishment, EFS Auvergne-Loire, 42023 Saint-Etienne, France
| | - Fabrice Cognasse
- GIMAP-EA3064, University of Lyon, Saint-Etienne, 42270 Saint-Priest-en-Jarez, France; French Blood Establishment, EFS Auvergne-Loire, 42023 Saint-Etienne, France
| | - Viviana Granados
- Department of Molecular Genetics, Saint-Etienne University Hospital, 42270 Saint-Priest-en-Jarez, France
| | - Mohsen Hassine
- Blood Bank of Monastir, F. Bourguiba University Hospital, 5000 Monastir, Tunisia
| | - Tahar Chakroun
- Regional Centre of Transfusion of Sousse, F. Hached University Hospital, 4000 Sousse, Tunisia
| | - Olivier Garraud
- GIMAP-EA3064, University of Lyon, Saint-Etienne, 42270 Saint-Priest-en-Jarez, France; National Institut of Blood Transfusion, 75739 Paris, France
| | - Sandrine Laradi
- GIMAP-EA3064, University of Lyon, Saint-Etienne, 42270 Saint-Priest-en-Jarez, France; French Blood Establishment, EFS Auvergne-Loire, 42023 Saint-Etienne, France.
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34
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Abstract
Generation of an effective immune response against foreign antigens requires two distinct molecular signals: a primary signal provided by the binding of antigen-specific T-cell receptor to peptide-MHC on antigen-presenting cells and a secondary signal delivered via the engagement of costimulatory molecules. Among various costimulatory signaling pathways, the interactions between CD40 and its ligand CD154 have been extensively investigated given their essential roles in the modulation of adaptive immunity. Here, we review current understanding of the role CD40/CD154 costimulation pathway has in alloimmunity, and summarize recent mechanistic and preclinical advances in the evaluation of candidate therapeutic approaches to target this receptor-ligand pair in transplantation.
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Affiliation(s)
- Tianshu Zhang
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Richard N Pierson
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
- Baltimore VA Medical Center, Baltimore, MD, USA
| | - Agnes M Azimzadeh
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
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35
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Abstract
PURPOSE OF REVIEW Stimulatory and inhibitory receptor signaling (cosignaling) on T cells is a critical component of T-cell responses that mediate graft rejection. The blockade of cosignaling pathways is an attractive strategy for preventing allogeneic T-cell responses. Here, we review the new studies that provide critical insight into the well studied CD28-CTLA-4 and CD40-CD40L cosignaling pathways, as well as the identification of novel cosignaling receptors that play a role in allogeneic T-cell responses. RECENT FINDINGS Recently, it has been appreciated that the CD28-CTLA-4 pathway has unique roles on specific T-cell subsets, particularly on forkhead box P3 (FoxP3)+ regulatory T cell (Treg) and T helper 17 (Th17) cells. New insight has been provided into the mechanism by which CD40-CD154 blockade elicits FoxP3+ Treg conversion and memory T cells elicit CD40-independent alloantibody responses. Finally, several novel cosignaling pathways have been demonstrated to be important to graft-specific T cells, including CD160, signaling lymphocytic activation molecule family member 2B4, T-cell Ig mucin 4, and the Notch receptor. SUMMARY Recent work has provided more granular understanding of the CD28-CTLA-4 and CD40-CD154 pathways on T-cell subsets, and provided important insight into the generation and maintenance of FoxP3+ Treg. This information, as well as the characterization of novel transplantation-relevant cosignaling pathways, has implications for the modulation of alloreactive T-cell responses.
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36
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Higginbotham L, Mathews D, Breeden CA, Song M, Farris AB, Larsen CP, Ford ML, Lutz AJ, Tector M, Newell KA, Tector AJ, Adams AB. Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model. Xenotransplantation 2015. [PMID: 25847130 DOI: 10.1111/xen.12166.pre-transplant] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
Xenotransplantation has the potential to alleviate the organ shortage that prevents many patients with end-stage renal disease from enjoying the benefits of kidney transplantation. Despite significant advances in other models, pig-to-primate kidney xenotransplantation has met limited success. Preformed anti-pig antibodies are an important component of the xenogeneic immune response. To address this, we screened a cohort of 34 rhesus macaques for anti-pig antibody levels. We then selected animals with both low and high titers of anti-pig antibodies to proceed with kidney transplant from galactose-α1,3-galactose knockout/CD55 transgenic pig donors. All animals received T-cell depletion followed by maintenance therapy with costimulation blockade (either anti-CD154 mAb or belatacept), mycophenolate mofetil, and steroid. The animal with the high titer of anti-pig antibody rejected the kidney xenograft within the first week. Low-titer animals treated with anti-CD154 antibody, but not belatacept exhibited prolonged kidney xenograft survival (>133 and >126 vs. 14 and 21 days, respectively). Long-term surviving animals treated with the anti-CD154-based regimen continue to have normal kidney function and preserved renal architecture without evidence of rejection on biopsies sampled at day 100. This description of the longest reported survival of pig-to-non-human primate kidney xenotransplantation, now >125 days, provides promise for further study and potential clinical translation.
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Affiliation(s)
- Laura Higginbotham
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Dave Mathews
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Cynthia A Breeden
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Mingqing Song
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Alton Brad Farris
- Anatomic Pathology, Emory University School of Medicine, Atlanta, GA, USA
| | - Christian P Larsen
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Mandy L Ford
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Andrew J Lutz
- Department of Surgery, Indiana University Health Transplant Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Matthew Tector
- Indiana University Health Transplant Department, Indianapolis, IN, USA
| | - Kenneth A Newell
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - A Joseph Tector
- Department of Surgery, Indiana University Health Transplant Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andrew B Adams
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
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Higginbotham L, Mathews D, Breeden CA, Song M, Farris AB, Larsen CP, Ford ML, Lutz AJ, Tector M, Newell KA, Tector AJ, Adams AB. Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model. Xenotransplantation 2015; 22:221-30. [PMID: 25847130 DOI: 10.1111/xen.12166] [Citation(s) in RCA: 172] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 02/08/2015] [Indexed: 12/13/2022]
Abstract
Xenotransplantation has the potential to alleviate the organ shortage that prevents many patients with end-stage renal disease from enjoying the benefits of kidney transplantation. Despite significant advances in other models, pig-to-primate kidney xenotransplantation has met limited success. Preformed anti-pig antibodies are an important component of the xenogeneic immune response. To address this, we screened a cohort of 34 rhesus macaques for anti-pig antibody levels. We then selected animals with both low and high titers of anti-pig antibodies to proceed with kidney transplant from galactose-α1,3-galactose knockout/CD55 transgenic pig donors. All animals received T-cell depletion followed by maintenance therapy with costimulation blockade (either anti-CD154 mAb or belatacept), mycophenolate mofetil, and steroid. The animal with the high titer of anti-pig antibody rejected the kidney xenograft within the first week. Low-titer animals treated with anti-CD154 antibody, but not belatacept exhibited prolonged kidney xenograft survival (>133 and >126 vs. 14 and 21 days, respectively). Long-term surviving animals treated with the anti-CD154-based regimen continue to have normal kidney function and preserved renal architecture without evidence of rejection on biopsies sampled at day 100. This description of the longest reported survival of pig-to-non-human primate kidney xenotransplantation, now >125 days, provides promise for further study and potential clinical translation.
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Affiliation(s)
- Laura Higginbotham
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Dave Mathews
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Cynthia A Breeden
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Mingqing Song
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Alton Brad Farris
- Anatomic Pathology, Emory University School of Medicine, Atlanta, GA, USA
| | - Christian P Larsen
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Mandy L Ford
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - Andrew J Lutz
- Department of Surgery, Indiana University Health Transplant Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Matthew Tector
- Indiana University Health Transplant Department, Indianapolis, IN, USA
| | - Kenneth A Newell
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
| | - A Joseph Tector
- Department of Surgery, Indiana University Health Transplant Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Andrew B Adams
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
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Pinelli DF, Ford ML. Novel insights into anti-CD40/CD154 immunotherapy in transplant tolerance. Immunotherapy 2015; 7:399-410. [PMID: 25917630 PMCID: PMC5441999 DOI: 10.2217/imt.15.1] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Since the discovery of the CD40-CD154 costimulatory pathway and its critical role in the adaptive immune response, there has been considerable interest in therapeutically targeting this interaction with monoclonal antibodies in transplantation. Unfortunately, initial promise in animal models gave way to disappointment in clinical trials following a number of thromboembolic complications. However, recent mechanistic studies have identified the mechanism of these adverse events, as well as detailed a myriad of interactions between CD40 and CD154 on a wide variety of immune cell types and the critical role of this pathway in generating both humoral and cell-mediated alloreactive responses. This has led to resurgence in interest and the potential resurrection of anti-CD154 and anti-CD40 antibodies as clinically viable therapeutic options.
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Affiliation(s)
| | - Mandy L. Ford
- Emory Transplant Center, Emory University, Atlanta, GA
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Vogel IT, Gool SWV, Ceuppens JL. CD28/CTLA-4/B7 and CD40/CD40L costimulation and activation of regulatory T cells. World J Immunol 2014; 4:63-77. [DOI: 10.5411/wji.v4.i2.63] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 05/12/2014] [Accepted: 06/11/2014] [Indexed: 02/05/2023] Open
Abstract
Costimulatory signals are crucial for T cell activation. Attempts to block costimulatory pathways have been effective in preventing unwanted immune reactions. In particular, blocking the CD28/cytotoxic T lymphocyte antigen (CTLA)-4/B7 interaction (using CTLA-4Ig) and the CD40/CD40L interaction (using anti-CD40L antibodies) prevents T cell mediated autoimmune diseases, transplant rejection and graft vs host disease in experimental models. Moreover, CTLA-4Ig is in clinical use to treat rheumatoid arthritis (abatacept) and to prevent rejection of renal transplants (belatacept). Under certain experimental conditions, this treatment can even result in tolerance. Surprisingly, the underlying mechanisms of immune modulation are still not completely understood. We here discuss the evidence that costimulation blockade differentially affects effector T cells (Teff) and regulatory T cells (Treg). The latter are required to control inappropriate and unwanted immune responses, and their activity often contributes to tolerance induction and maintenance. Unfortunately, our knowledge on the costimulatory requirements of Treg cells is very limited. We therefore summarize the current understanding of the costimulatory requirements of Treg cells, and elaborate on the effect of anti-CD40L antibody and CTLA-4Ig treatment on Treg cell activity. In this context, we point out that the outcome of a treatment aiming at blocking the CD28/CTLA-4/B7 costimulatory interaction can vary with dosing, timing and underlying immunopathology.
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Xie JH, Yamniuk AP, Borowski V, Kuhn R, Susulic V, Rex-Rabe S, Yang X, Zhou X, Zhang Y, Gillooly K, Brosius R, Ravishankar R, Waggie K, Mink K, Price L, Rehfuss R, Tamura J, An Y, Cheng L, Abramczyk B, Ignatovich O, Drew P, Grant S, Bryson JW, Suchard S, Salter-Cid L, Nadler S, Suri A. Engineering of a Novel Anti-CD40L Domain Antibody for Treatment of Autoimmune Diseases. THE JOURNAL OF IMMUNOLOGY 2014; 192:4083-92. [DOI: 10.4049/jimmunol.1303239] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Abstract
The myriad of co-stimulatory signals expressed, or induced, upon T-cell activation suggests that these signalling pathways shape the character and magnitude of the resulting autoreactive or alloreactive T-cell responses during autoimmunity or transplantation, respectively. Reducing pathological T-cell responses by targeting T-cell co-stimulatory pathways has met with therapeutic success in many instances, but challenges remain. In this Review, we discuss the T-cell co-stimulatory molecules that are known to have critical roles during T-cell activation, expansion, and differentiation. We also outline the functional importance of T-cell co-stimulatory molecules in transplantation, tolerance and autoimmunity, and we describe how therapeutic blockade of these pathways might be harnessed to manipulate the immune response to prevent or attenuate pathological immune responses. Ultimately, understanding the interplay between individual co-stimulatory and co-inhibitory pathways engaged during T-cell activation and differentiation will lead to rational and targeted therapeutic interventions to manipulate T-cell responses and improve clinical outcomes.
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Affiliation(s)
- Mandy L Ford
- The Emory Transplant Center, Emory University, 101 Woodruff Circle, Woodruff Memorial Research Building Suite 5105, Atlanta, GA 30322, USA
| | - Andrew B Adams
- The Emory Transplant Center, Emory University, 101 Woodruff Circle, Woodruff Memorial Research Building Suite 5105, Atlanta, GA 30322, USA
| | - Thomas C Pearson
- The Emory Transplant Center, Emory University, 101 Woodruff Circle, Woodruff Memorial Research Building Suite 5105, Atlanta, GA 30322, USA
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