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Anwar IJ, DeLaura I, Ladowski JM, Schilirò D, Gao Q, Manook M, Yoon J, Belloni R, Park A, Schuster DJ, Song M, Lin L, Farris AB, Magnani D, Williams K, Kwun J, Knechtle SJ. CD154 blockade effectively controls antibody-mediated rejection in highly sensitized nonhuman primate kidney transplant recipients. Sci Transl Med 2025; 17:eadn8130. [PMID: 39742504 PMCID: PMC11797747 DOI: 10.1126/scitranslmed.adn8130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 12/05/2024] [Indexed: 01/03/2025]
Abstract
Current desensitization and maintenance immunosuppression regimens for kidney transplantation in sensitized individuals show limited ability to control the posttransplant humoral response, resulting in high rates of antibody-mediated rejection (ABMR) and graft failure. Here, we showed that anti-CD154 monoclonal antibody (mAb)-based immunosuppression more effectively controlled allograft rejection and humoral rebound in a highly sensitized nonhuman primate kidney transplantation model compared with tacrolimus-based standard-of-care (SOC) immunosuppression. Desensitization with an anti-CD154 mAb (5C8) and a proteasome inhibitor led to decreased donor-specific antibodies (DSAs) and disruption of lymph node germinal centers with reduction of proliferating, memory, and class-switched B cells as well as T follicular helper cells. After transplant, the nonhuman primates maintained on 5C8-based immunosuppression had significantly better survival compared with those maintained on SOC immunosuppression (135.2 days versus 32.8 days, P = 0.013). The 5C8-treated group demonstrated better suppression of DSAs after transplant, more robust suppression of B cell populations, and better induction of regulatory T cells. Fewer infectious and welfare complications, including viral reactivation and weight loss, were also observed with 5C8-based immunosuppression compared with SOC immunosuppression. Therefore, anti-CD154 mAbs may improve kidney transplant outcomes through better control of posttransplant immune responses. The superior efficacy of anti-CD154 mAb-based immunosuppression over tacrolimus-based SOC seen in this highly sensitized NHP transplant model suggests that anti-CD154 mAbs could potentially be used to desensitize and treat highly sensitized patients receiving kidney transplantation.
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Affiliation(s)
- Imran J. Anwar
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Isabel DeLaura
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Joseph M. Ladowski
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Davide Schilirò
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Qimeng Gao
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Miriam Manook
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Janghoon Yoon
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Rafaela Belloni
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Angela Park
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Daniel J. Schuster
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Mingqing Song
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Lin Lin
- Department of Biostatistics & Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA
| | - Alton B. Farris
- Department of Pathology, Emory University School of Medicine; Atlanta, GA 30322, USA
| | - Diogo Magnani
- Nonhuman Primate reagent Resource, UMass Chan Medical School, Worcester, MA 01605, USA
| | - Kyha Williams
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Jean Kwun
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
| | - Stuart J. Knechtle
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
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Chuang ST, Alcazar O, Watts B, Abdulreda MH, Buchwald P. Small-molecule inhibitors of the CD40-CD40L costimulatory interaction are effective in pancreatic islet transplantation and prevention of type 1 diabetes models. Front Immunol 2024; 15:1484425. [PMID: 39606229 PMCID: PMC11599200 DOI: 10.3389/fimmu.2024.1484425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
As part of our work to develop small-molecule inhibitors (SMIs) of the CD40-CD40L(CD154) costimulatory protein-protein interaction, here, we describe the ability of two of our most promising SMIs, DRI-C21041 and DRI-C21095, to prolong the survival and function of islet allografts in two murine models of islet transplantation (under the kidney capsule and in the anterior chamber of the eye) and to prevent autoimmune type 1 diabetes (T1D) onset in NOD mice. In both transplant models, a significant portion of islet allografts (50%-80%) remained intact and functional long after terminating treatment, suggesting the possibility of inducing operational immune tolerance via inhibition of the CD40-CD40L axis. SMI-treated mice maintained the structural integrity and function of their islet allografts with concomitant reduction in immune cell infiltration as evidenced by direct longitudinal imaging in situ. Furthermore, in female NODs, three-month SMI treatment reduced the incidence of diabetes from 80% to 60% (DRI-C21041) and 25% (DRI-C21095). These results (i) demonstrate the susceptibility of this TNF superfamily protein-protein interaction to small-molecule inhibition, (ii) confirm the in vivo therapeutic potential of these SMIs of a critical immune checkpoint, and (iii) reaffirm the therapeutic promise of CD40-CD40L blockade in islet transplantation and T1D prevention. Thus, CD40L-targeting SMIs could ultimately lead to alternative immunomodulatory therapeutics for transplant recipients and prevention of autoimmune diseases that are safer, less immunogenic, more controllable (shorter half-lives), and more patient-friendly (i.e., suitable for oral administration, which makes them easier to administer) than corresponding antibody-based interventions.
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Affiliation(s)
- Sung-Ting Chuang
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Oscar Alcazar
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Brandon Watts
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Midhat H. Abdulreda
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
- Department of Ophthalmology, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
- Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL, United States
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Saha A, Palchaudhuri R, Lanieri L, Hyzy S, Riddle MJ, Panthera J, Eide CR, Tolar J, Panoskaltsis-Mortari A, Gorfinkel L, Tkachev V, Gerdemann U, Alvarez-Calderon F, Palato ER, MacMillan ML, Wagner JE, Kean LS, Osborn MJ, Kiem HP, Scadden DT, Olson LM, Blazar BR. Alloengraftment without significant toxicity or GVHD in CD45 antibody-drug conjugate-conditioned Fanconi anemia mice. Blood 2024; 143:2201-2216. [PMID: 38447038 PMCID: PMC11143525 DOI: 10.1182/blood.2023023549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 02/09/2024] [Accepted: 02/25/2024] [Indexed: 03/08/2024] Open
Abstract
ABSTRACT Fanconi anemia (FA) is an inherited DNA repair disorder characterized by bone marrow (BM) failure, developmental abnormalities, myelodysplasia, leukemia, and solid tumor predisposition. Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a mainstay treatment, is limited by conditioning regimen-related toxicity and graft-versus-host disease (GVHD). Antibody-drug conjugates (ADCs) targeting hematopoietic stem cells (HSCs) can open marrow niches permitting donor stem cell alloengraftment. Here, we report that single dose anti-mouse CD45-targeted ADC (CD45-ADC) facilitated stable, multilineage chimerism in 3 distinct FA mouse models representing 90% of FA complementation groups. CD45-ADC profoundly depleted host stem cell enriched Lineage-Sca1+cKit+ cells within 48 hours. Fanca-/- recipients of minor-mismatched BM and single dose CD45-ADC had peripheral blood (PB) mean donor chimerism >90%; donor HSCs alloengraftment was verified in secondary recipients. In Fancc-/- and Fancg-/- recipients of fully allogeneic grafts, PB mean donor chimerism was 60% to 80% and 70% to 80%, respectively. The mean percent donor chimerism in BM and spleen mirrored PB results. CD45-ADC-conditioned mice did not have clinical toxicity. A transient <2.5-fold increase in hepatocellular enzymes and mild-to-moderate histopathological changes were seen. Under GVHD allo-HSCT conditions, wild-type and Fanca-/- recipients of CD45-ADC had markedly reduced GVHD lethality compared with lethal irradiation. Moreover, single dose anti-human CD45-ADC given to rhesus macaque nonhuman primates on days -6 or -10 was at least as myeloablative as lethal irradiation. These data suggest that CD45-ADC can potently promote donor alloengraftment and hematopoiesis without significant toxicity or severe GVHD, as seen with lethal irradiation, providing strong support for clinical trial considerations in highly vulnerable patients with FA.
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Affiliation(s)
- Asim Saha
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | | | | | | | - Megan J. Riddle
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Jamie Panthera
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Cindy R. Eide
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Jakub Tolar
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Angela Panoskaltsis-Mortari
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Lev Gorfinkel
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA
| | - Victor Tkachev
- Massachusetts General Hospital Center for Transplantation Sciences, Mass General Brigham and Massachusetts General Hospital, Boston, MA
| | - Ulrike Gerdemann
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA
| | | | | | - Margaret L. MacMillan
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - John E. Wagner
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Leslie S. Kean
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA
| | - Mark J. Osborn
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Hans-Peter Kiem
- Department of Medicine, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA
| | - David T. Scadden
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA
- Harvard Stem Cell Institute, Cambridge, MA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA
| | | | - Bruce R. Blazar
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics and Masonic Cancer Center, University of Minnesota, Minneapolis, MN
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Schroth SL, Jones RTL, Thorp EB. Alloantigen Infusion Activates the Transcriptome of Type 2 Conventional Dendritic Cells. Immunohorizons 2023; 7:683-693. [PMID: 37855737 PMCID: PMC10615655 DOI: 10.4049/immunohorizons.2300067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 09/13/2023] [Indexed: 10/20/2023] Open
Abstract
Recent studies have revealed novel molecular mechanisms by which innate monocytic cells acutely recognize and respond to alloantigen with significance to allograft rejection and tolerance. What remains unclear is the single-cell heterogeneity of the innate alloresponse, particularly the contribution of dendritic cell (DC) subsets. To investigate the response of these cells to exposure of alloantigen, C57BL/6J mice were administered live allogenic BALB/cJ splenic murine cells versus isogenic cells. In parallel, we infused apoptotic allogenic and isogenic cells, which have been reported to modulate immunity. Forty-eight hours after injection, recipient spleens were harvested, enriched for DCs, and subjected to single-cell mRNA sequencing. Injection of live cells induced a greater transcriptional change across DC subsets compared with apoptotic cells. In the setting of live cell infusion, type 2 conventional DCs (cDC2s) were most transcriptionally responsive with a Ccr2+ cDC2 subcluster uniquely responding to the presence of alloantigen compared with the isogenic control. In vitro experimentation confirmed unique activation of CCR2+ cDC2s following alloantigen exposure. Candidate receptors of allorecognition in other innate populations were interrogated and A type paired Ig-like receptors were found to be increased in the cDC2 population following alloexposure. These results illuminate previously unclear distinctions between therapeutic infusions of live versus apoptotic allogenic cells and suggest a role for cDC2s in innate allorecognition. More critically, these studies allow for future interrogation of the transcriptional response of immune cells in the setting of alloantigen exposure in vivo, encouraging assessment of novel pathways and previously unexamined receptors in this setting.
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Affiliation(s)
- Samantha L. Schroth
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Rebecca T. L. Jones
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Edward B. Thorp
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL
- Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
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Saha A, Blazar BR. Antibody based conditioning for allogeneic hematopoietic stem cell transplantation. Front Immunol 2022; 13:1031334. [PMID: 36341432 PMCID: PMC9632731 DOI: 10.3389/fimmu.2022.1031334] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 10/10/2022] [Indexed: 08/25/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for many patients with hematological malignancies and nonmalignant hematopoietic disorders. To achieve stable engraftment of donor hematopoietic stem cells (HSCs), recipient HSC deletion is needed to create space for incoming donor HSCs and donor HSCs must escape immune rejection by the recipient. Conventional allo-HSCT requires high dose of irradiation and/or chemotherapy to produce sufficient host stem cell and immune system ablation to permit donor HSC engraftment. However, these procedures also result in nonspecific tissue injury that can cause short- and long-term adverse effects as well as incite and amplify graft-versus-host-disease (GVHD). The delivery of targeted radiotherapy to hematopoietic tissues with the use of a radioimmunoconjugate (ROIC) as a part of transplant preparative regimen has shown clinical benefits. ROIC clinical data provide evidence for decreased relapse without increased transplant-related mortality by delivering higher targeted radiation to sites of malignancy than when given in a nontargeted fashion. An alternative approach to allo-HSCT has been developed and tested in preclinical mouse models in which nonmyeloablative preconditioning with low dose of the alkylating agent (busulfan) or lower systemic dose of irradiation combined with co-stimulatory pathway blockade (CTLA4-Ig, anti-CD40L monoclonal antibody) and/or immunosuppressive drugs have been used. Under these conditions, mixed chimerism and transplantation tolerance to fully MHC mismatched donor marrow was observed. Recently, several novel proof-of-concept antibody-mediated preconditioning methods have been developed that can selectively target hematopoietic stem and immune cells with minimal overall toxicity. Antibody-drug-conjugate (ADC) combined with reduced intensity conditioning or high dose ADC as single dose monotherapy have shown promise for allo-HSCT in preclinical models. The purpose of the current review is to discuss the literature exploring antibody-based conditioning that includes native antibody, radiolabeled antibody conjugates, and ADC for allo-HSCT.
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Affiliation(s)
- Asim Saha
- Division of Blood & Marrow Transplant & Cellular Therapy, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
| | - Bruce R. Blazar
- Division of Blood & Marrow Transplant & Cellular Therapy, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
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6
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Saha A, Hyzy S, Lamothe T, Hammond K, Clark N, Lanieri L, Bhattarai P, Palchaudhuri R, Gillard GO, Proctor J, Riddle MJ, Panoskaltsis-Mortari A, MacMillan ML, Wagner JE, Kiem HP, Olson LM, Blazar BR. A CD45-targeted antibody-drug conjugate successfully conditions for allogeneic hematopoietic stem cell transplantation in mice. Blood 2022; 139:1743-1759. [PMID: 34986233 PMCID: PMC8931510 DOI: 10.1182/blood.2021012366] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 11/29/2021] [Indexed: 12/18/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment of patients with nonmalignant or malignant blood disorders. Its success has been limited by graft-versus-host disease (GVHD). Current systemic nontargeted conditioning regimens mediate tissue injury and potentially incite and amplify GVHD, limiting the use of this potentially curative treatment beyond malignant disorders. Minimizing systemic nontargeted conditioning while achieving alloengraftment without global immune suppression is highly desirable. Antibody-drug-conjugates (ADCs) targeting hematopoietic cells can specifically deplete host stem and immune cells and enable alloengraftment. We report an anti-mouse CD45-targeted-ADC (CD45-ADC) that facilitates stable murine multilineage donor cell engraftment. Conditioning with CD45-ADC (3 mg/kg) was effective as a single agent in both congenic and minor-mismatch transplant models resulting in full donor chimerism comparable to lethal total body irradiation (TBI). In an MHC-disparate allo-HSCT model, pretransplant CD45-ADC (3 mg/kg) combined with low-dose TBI (150 cGy) and a short course of costimulatory blockade with anti-CD40 ligand antibody enabled 89% of recipients to achieve stable alloengraftment (mean value: 72%). When CD45-ADC was combined with pretransplant TBI (50 cGy) and posttransplant rapamycin, cyclophosphamide (Cytoxan), or a JAK inhibitor, 90% to 100% of recipients achieved stable chimerism (mean: 77%, 59%, 78%, respectively). At a higher dose (5 mg/kg), CD45-ADC as a single agent was sufficient for rapid, high-level multilineage chimerism sustained through the 22 weeks observation period. Therefore, CD45-ADC has the potential utility to confer the benefit of fully myeloablative conditioning but with substantially reduced toxicity when given as a single agent or at lower doses in conjunction with reduced-intensity conditioning.
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Affiliation(s)
- Asim Saha
- Division of Blood & Marrow Transplant & Cellular Therapy, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN
| | | | | | | | | | | | | | | | | | | | - Megan J Riddle
- Division of Blood & Marrow Transplant & Cellular Therapy, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN
| | - Angela Panoskaltsis-Mortari
- Division of Blood & Marrow Transplant & Cellular Therapy, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN
| | - Margaret L MacMillan
- Division of Blood & Marrow Transplant & Cellular Therapy, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN
| | - John E Wagner
- Division of Blood & Marrow Transplant & Cellular Therapy, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN
| | - Hans-Peter Kiem
- Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, WA
| | | | - Bruce R Blazar
- Division of Blood & Marrow Transplant & Cellular Therapy, Masonic Cancer Center and Department of Pediatrics, University of Minnesota, Minneapolis, MN
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Shaw BI, Ord JR, Nobuhara C, Luo X. Cellular Therapies in Solid Organ Allotransplantation: Promise and Pitfalls. Front Immunol 2021; 12:714723. [PMID: 34526991 PMCID: PMC8435835 DOI: 10.3389/fimmu.2021.714723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/04/2021] [Indexed: 12/30/2022] Open
Abstract
Donor specific transfusions have been the basis of tolerance inducing protocols since Peter Medawar showed that it was experimentally feasible in the 1950s. Though trials of cellular therapies have become increasingly common in solid organ transplantation, they have not become standard practice. Additionally, whereas some protocols have focused on cellular therapies as a method for donor antigen delivery-thought to promote tolerance in and of itself in the correct immunologic context-other approaches have alternatively focused on the intrinsic immunosuppressive properties of the certain cell types with less emphasis on their origin, including mesenchymal stem cells, regulatory T cells, and regulatory dendritic cells. Regardless of intent, all cellular therapies must contend with the potential that introducing donor antigen in a new context will lead to sensitization. In this review, we focus on the variety of cellular therapies that have been applied in human trials and non-human primate models, describe their efficacy, highlight data regarding their potential for sensitization, and discuss opportunities for cellular therapies within our current understanding of the immune landscape.
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Affiliation(s)
- Brian I. Shaw
- Department of Surgery, Duke University, Durham, NC, United States
| | - Jeffrey R. Ord
- School of Medicine, Duke University, Durham, NC, United States
| | - Chloe Nobuhara
- School of Medicine, Duke University, Durham, NC, United States
| | - Xunrong Luo
- Department of Medicine, Division of Nephrology, Duke University, Durham, NC, United States
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8
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Ordikhani F, Pothula V, Sanchez-Tarjuelo R, Jordan S, Ochando J. Macrophages in Organ Transplantation. Front Immunol 2020; 11:582939. [PMID: 33329555 PMCID: PMC7734247 DOI: 10.3389/fimmu.2020.582939] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
Current immunosuppressive therapy has led to excellent short-term survival rates in organ transplantation. However, long-term graft survival rates are suboptimal, and a vast number of allografts are gradually lost in the clinic. An increasing number of animal and clinical studies have demonstrated that monocytes and macrophages play a pivotal role in graft rejection, as these mononuclear phagocytic cells recognize alloantigens and trigger an inflammatory cascade that activate the adaptive immune response. Moreover, recent studies suggest that monocytes acquire a feature of memory recall response that is associated with a potent immune response. This form of memory is called “trained immunity,” and it is retained by mechanisms of epigenetic and metabolic changes in innate immune cells after exposure to particular ligands, which have a direct impact in allograft rejection. In this review article, we highlight the role of monocytes and macrophages in organ transplantation and summarize therapeutic approaches to promote tolerance through manipulation of monocytes and macrophages. These strategies may open new therapeutic opportunities to increase long-term transplant survival rates in the clinic.
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Affiliation(s)
- Farideh Ordikhani
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Venu Pothula
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Rodrigo Sanchez-Tarjuelo
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Stefan Jordan
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Jordi Ochando
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
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9
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Gill RG, Burrack AL. Diverse Routes of Allograft Tolerance Disruption by Memory T Cells. Front Immunol 2020; 11:580483. [PMID: 33117387 PMCID: PMC7578217 DOI: 10.3389/fimmu.2020.580483] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 09/24/2020] [Indexed: 12/11/2022] Open
Abstract
Memory T lymphocytes constitute a significant problem in tissue and organ transplantation due their contribution to early rejection and their relative resistance to tolerance-promoting therapies. Memory cells generated by environmental antigen exposure, as with T cells in general, harbor a high frequency of T cell receptors (TCR) spontaneously cross-reacting with allogeneic major histocompatibility complex (MHC) molecules. This phenomenon, known as ‘heterologous’ immunity, is thought to be a key barrier to transplant tolerance induction since such memory cells can potentially react directly with essentially any prospective allograft. In this review, we describe two additional concepts that expand this commonly held view of how memory cells contribute to transplant immunity and tolerance disruption. Firstly, autoimmunity is an additional response that can comprise an endogenously generated form of heterologous alloimmunity. However, unlike heterologous immunity generated as a byproduct of indiscriminate antigen sensitization, autoimmunity can generate T cells that have the unusual potential to interact with the graft either through the recognition of graft-bearing autoantigens or by their cross-reactive (heterologous) alloimmune specificity to MHC molecules. Moreover, we describe an additional pathway, independent of significant heterologous immunity, whereby immune memory to vaccine- or pathogen-induced antigens also may impair tolerance induction. This latter form of immune recognition indirectly disrupts tolerance by the licensing of naïve alloreactive T cells by vaccine/pathogen directed memory cells recognizing the same antigen-presenting cell in vivo. Thus, there appear to be recognition pathways beyond typical heterologous immunity through which memory T cells can directly or indirectly impact allograft immunity and tolerance.
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Affiliation(s)
- Ronald G Gill
- Departments of Surgery and Immunology and Microbiology, University of Colorado Denver, Aurora, CO, United States
| | - Adam L Burrack
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
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10
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Emoto S, Shibasaki S, Nagatsu A, Goto R, Ono H, Fukasaku Y, Igarashi R, Ota T, Fukai M, Shimamura T, Saiga K, Taketomi A, Murakami M, Todo S, Yamashita K. Triazolopyrimidine derivative NK026680 and donor-specific transfusion induces CD4 +CD25 +Foxp3 + T cells and ameliorates allograft rejection in an antigen-specific manner. Transpl Immunol 2020; 65:101338. [PMID: 33022372 DOI: 10.1016/j.trim.2020.101338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 10/02/2020] [Accepted: 10/02/2020] [Indexed: 11/19/2022]
Abstract
We have previously demonstrated the unique properties of a new triazolopyrimidine derivative, NK026680, which exerts immunosuppressive effects in rat heart transplant model and confers tolerogeneic properties on ex vivo-conditioned dendritic cells in mice. We herein demonstrate that NK026680 promotes the expansion of regulatory T cells (Tregs) with potent immunoregulatory effects when used in combination with donor-specific transfusion (DST). BALB/c (H-2d) heart graft were transplanted into C57BL/6 (H-2b) mice following intravenous injection of donor splenocytes (DST) and oral administration of NK026680. The NK026680 plus DST treatment markedly prolonged the survival time of the donor-graft, but not that of the 3rd party-graft (C3H; H-2k). Treg cells in the recipient spleen on day 0 expanded when stimulated with donor-antigens in vivo and in vitro. After heart transplantation, Treg cells accumulated into the graft and increased in the spleen. NK026680 plus DST also decreased activated CD8+ T cells in the spleen and inhibited infiltration of CD8+ T cells into the graft. Depletion of CD25+ cells inhibited the graft prolonging effect of the NK026680 plus DST treatment. NK026680 administration together with DST induces potent immunoregulatory effects in an antigen-specific manner, likely due to the in vivo generation of donor-specific Tregs.
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Affiliation(s)
- Shin Emoto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Susumu Shibasaki
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Akihisa Nagatsu
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Ryoichi Goto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Hitoshi Ono
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Yasutomo Fukasaku
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Rumi Igarashi
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Takuji Ota
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Moto Fukai
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan.
| | - Kan Saiga
- Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Masaaki Murakami
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
| | - Satoru Todo
- Research Institute of St. Mary's Hospital, Kurume, Japan.
| | - Kenichiro Yamashita
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
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11
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Schönberg A, Hamdorf M, Bock F. Immunomodulatory Strategies Targeting Dendritic Cells to Improve Corneal Graft Survival. J Clin Med 2020; 9:E1280. [PMID: 32354200 PMCID: PMC7287922 DOI: 10.3390/jcm9051280] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/08/2020] [Accepted: 04/21/2020] [Indexed: 12/16/2022] Open
Abstract
Even though the cornea is regarded as an immune-privileged tissue, transplantation always comes with the risk of rejection due to mismatches between donor and recipient. It is common sense that an alternative to corticosteroids as the current gold standard for treatment of corneal transplantation is needed. Since blood and lymphatic vessels have been identified as a severe risk factor for corneal allograft survival, much research has focused on vessel regression or inhibition of hem- and lymphangiogenesis in general. However, lymphatic vessels have been identified as required for the inflammation's resolution. Therefore, targeting other players of corneal engraftment could reveal new therapeutic strategies. The establishment of a tolerogenic microenvironment at the graft site would leave the recipient with the ability to manage pathogenic conditions independent from transplantation. Dendritic cells (DCs) as the central player of the immune system represent a target that allows the induction of tolerogenic mechanisms by many different strategies. These strategies are reviewed in this article with regard to their success in corneal transplantation.
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Affiliation(s)
- Alfrun Schönberg
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (M.H.)
| | - Matthias Hamdorf
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (M.H.)
| | - Felix Bock
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (M.H.)
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany
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12
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Yeung MY, Grimmig T, Sayegh MH. Costimulation Blockade in Transplantation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1189:267-312. [PMID: 31758538 DOI: 10.1007/978-981-32-9717-3_10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
T cells play a pivotal role in orchestrating immune responses directed against a foreign (allogeneic) graft. For T cells to become fully activated, the T-cell receptor (TCR) must interact with the major histocompatibility complex (MHC) plus peptide complex on antigen-presenting cells (APCs), followed by a second "positive" costimulatory signal. In the absence of this second signal, T cells become anergic or undergo deletion. By blocking positive costimulatory signaling, T-cell allo-responses can be aborted, thus preventing graft rejection and promoting long-term allograft survival and possibly tolerance (Alegre ML, Najafian N, Curr Mol Med 6:843-857, 2006; Li XC, Rothstein DM, Sayegh MH, Immunol Rev 229:271-293, 2009). In addition, costimulatory molecules can provide negative "coinhibitory" signals that inhibit T-cell activation and terminate immune responses; strategies to promote these pathways can also lead to graft tolerance (Boenisch O, Sayegh MH, Najafian N, Curr Opin Organ Transplant 13:373-378, 2008). However, T-cell costimulation involves an incredibly complex array of interactions that may act simultaneously or at different times in the immune response and whose relative importance varies depending on the different T-cell subsets and activation status. In transplantation, the presence of foreign alloantigen incites not only destructive T effector cells but also protective regulatory T cells, the balance of which ultimately determines the fate of the allograft (Lechler RI, Garden OA, Turka LA, Nat Rev Immunol 3:147-158, 2003). Since the processes of alloantigen-specific rejection and regulation both require activation of T cells, costimulatory interactions may have opposing or synergistic roles depending on the cell being targeted. Such complexities present both challenges and opportunities in targeting T-cell costimulatory pathways for therapeutic purposes. In this chapter, we summarize our current knowledge of the various costimulatory pathways in transplantation and review the current state and challenges of harnessing these pathways to promote graft tolerance (summarized in Table 10.1).
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Affiliation(s)
- Melissa Y Yeung
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, MA, USA. .,Harvard Medical School, Boston, MA, USA.
| | - Tanja Grimmig
- Department of Surgery, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg, Germany
| | - Mohamed H Sayegh
- Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Department of Medicine and Immunology, American University of Beirut, Beirut, Lebanon
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13
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Fitch Z, Schmitz R, Kwun J, Hering B, Madsen J, Knechtle SJ. Transplant research in nonhuman primates to evaluate clinically relevant immune strategies in organ transplantation. Transplant Rev (Orlando) 2019; 33:115-129. [PMID: 31027947 PMCID: PMC6599548 DOI: 10.1016/j.trre.2019.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 03/08/2019] [Accepted: 03/26/2019] [Indexed: 12/27/2022]
Abstract
Research in transplant immunology using non-human primate (NHP) species to evaluate immunologic strategies to prevent rejection and prolong allograft survival has yielded results that have translated successfully into human organ transplant patient management. Other therapies have not proceeded to human translation due to failure in NHP testing, arguably sparing humans the futility and risk of such testing. The NHP transplant models are ethically necessary for drug development in this field and provide the closest analogue to human transplant patients available. The refinement of this resource with respect to colony MHC typing, reagent and assay development, and availability to the research community has greatly enhanced knowledge about transplant immunology and drug development.
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Affiliation(s)
- Zachary Fitch
- Department of Surgery, Duke Transplant Center, Durham, NC 27710, USA; Center for Transplantation Sciences, Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, White 510c, 55 Fruit Street, Boston, MA, USA
| | - Robin Schmitz
- Department of Surgery, Duke Transplant Center, Durham, NC 27710, USA
| | - Jean Kwun
- Department of Surgery, Duke Transplant Center, Durham, NC 27710, USA
| | - Bernhard Hering
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Joren Madsen
- Department of Surgery, Duke Transplant Center, Durham, NC 27710, USA
| | - Stuart J Knechtle
- Department of Surgery, Duke Transplant Center, Durham, NC 27710, USA.
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14
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Cisneros T, Dillard DW, Qu X, Arredondo-Guerrero J, Castro M, Schaffert S, Martin R, Esquivel CO, Krams SM, Martinez OM. Differential role of natural killer group 2D in recognition and cytotoxicity of hepatocyte-like cells derived from embryonic stem cells and induced pluripotent stem cells. Am J Transplant 2019; 19:1652-1662. [PMID: 30549427 PMCID: PMC6543818 DOI: 10.1111/ajt.15217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 11/28/2018] [Accepted: 11/30/2018] [Indexed: 01/25/2023]
Abstract
Stem cell-based approaches have the potential to address the organ shortage in transplantation. Whereas both embryonic stem cells and induced pluripotent stem cells have been utilized as cellular sources for differentiation and lineage specification, their relative ability to be recognized by immune effector cells is unclear. We determined the expression of immune recognition molecules on hepatocyte-like cells (HLC) generated from murine embryonic stem cells and induced pluripotent stem cells, compared to adult hepatocytes, and we evaluated the impact on recognition by natural killer (NK) cells. We report that HLC lack MHC class I expression, and that embryonic stem cell-derived HLC have higher expression of the NK cell activating ligands Rae1, H60, and Mult1 than induced pluripotent stem cell-derived HLC and adult hepatocytes. Moreover, the lack of MHC class I renders embryonic stem cell-derived HLC, and induced pluripotent stem cell-derived HLC, susceptible to killing by syngeneic and allogeneic NK cells. Both embryonic stem cell-derived HLC, and induced pluripotent stem cell-derived HLC, are killed by NK cells at higher levels than adult hepatocytes. Finally, we demonstrate that the NK cell activation receptor, NKG2D, plays a key role in NK cell cytotoxicity of embryonic stem cell-derived HLC, but not induced pluripotent stem cell-derived HLC.
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Affiliation(s)
- Trinidad Cisneros
- Stanford Immunology, Stanford University School of
Medicine, Stanford, CA, USA,Department of Surgery/Division of Abdominal
Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| | - Danielle W. Dillard
- Department of Surgery/Division of Abdominal
Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| | - Xiumei Qu
- Department of Surgery/Division of Abdominal
Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Martha Castro
- Stanford Immunology, Stanford University School of
Medicine, Stanford, CA, USA
| | - Steven Schaffert
- Stanford Center for Biomedical Informatics Research,
Stanford University School of Medicine, Stanford, CA, USA
| | - Renata Martin
- Department of Biology, Stanford University School of
Medicine, Stanford, CA, USA
| | - Carlos O. Esquivel
- Department of Surgery/Division of Abdominal
Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| | - Sheri M. Krams
- Stanford Immunology, Stanford University School of
Medicine, Stanford, CA, USA,Department of Surgery/Division of Abdominal
Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| | - Olivia M. Martinez
- Stanford Immunology, Stanford University School of
Medicine, Stanford, CA, USA,Department of Surgery/Division of Abdominal
Transplantation, Stanford University School of Medicine, Stanford, CA, USA
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15
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Jangalwe S, Kapoor VN, Xu J, Girnius N, Kennedy NJ, Edwards YJK, Welsh RM, Davis RJ, Brehm MA. Cutting Edge: Early Attrition of Memory T Cells during Inflammation and Costimulation Blockade Is Regulated Concurrently by Proapoptotic Proteins Fas and Bim. THE JOURNAL OF IMMUNOLOGY 2019; 202:647-651. [PMID: 30610162 DOI: 10.4049/jimmunol.1800278] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 12/06/2018] [Indexed: 11/19/2022]
Abstract
Apoptosis of CD8 T cells is an essential mechanism that maintains immune system homeostasis, prevents autoimmunity, and reduces immunopathology. CD8 T cell death also occurs early during the response to both inflammation and costimulation blockade (CoB). In this article, we studied the effects of a combined deficiency of Fas (extrinsic pathway) and Bim (intrinsic pathway) on early T cell attrition in response to lymphocytic choriomeningitis virus infection and during CoB during transplantation. Loss of Fas and Bim function in Bcl2l11-/-Faslpr/lpr mice inhibited apoptosis of T cells and prevented the early T cell attrition resulting from lymphocytic choriomeningitis virus infection. Bcl2l11-/-Faslpr/lpr mice were also resistant to prolonged allograft survival induced by CoB targeting the CD40-CD154 pathway. These results demonstrate that both extrinsic and intrinsic apoptosis pathways function concurrently to regulate T cell homeostasis during the early stages of immune responses and allograft survival during CoB.
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Affiliation(s)
- Sonal Jangalwe
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
| | - Varun N Kapoor
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Jia Xu
- IBM Watson Health, Cambridge, MA 02142
| | - Nomeda Girnius
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115; and.,Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115
| | - Norman J Kennedy
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
| | - Yvonne J K Edwards
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
| | - Raymond M Welsh
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605
| | - Roger J Davis
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
| | - Michael A Brehm
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605;
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16
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Hu Y, Zhou H, Gao B, Wang G, Wang Y. Role of regulatory T cells in CD47/donor-specific transfusion-induced immune tolerance in skin-heart transplantation mice. Transpl Infect Dis 2018; 21:e13012. [PMID: 30320937 DOI: 10.1111/tid.13012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 08/10/2018] [Accepted: 08/21/2018] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To explore the role of regulatory T (Treg ) cells in the establishment of immune tolerance induced by donor-specific transfusion (DST) in mice with skin-heart transplantation. METHODS C57BL/6 mice received DST of splenocytes from CD47+/+ or CD47-/- H-2bm1 mice or no DST 7 days before skin-heart transplantation from major histocompatibility complex class I-mismatched H-2bm1 donors. The number and proportion of Treg cells in graft and lymphoid organs were measured by flow cytometry (FACS) and immunohistochemistry (IHC). The inhibitory function of Treg cells and anti-donor T-cell responses were assessed by mixed lymphocyte reaction. RESULTS We observed that mean survival time (MST) of skin or heart graft was significantly longer in C57BL/6 mice which received DST from CD47+/+ H-2bm1 mice than from CD47-/- H-2bm1 mice. By FACS, we found that the number of Treg cells in spleen was increased significantly in mice which received CD47-/- DST compared to mice which received CD47+/+ DST. However, the percentages of Treg cells in total splenocytes and lymph node cells were significantly higher in mice that received CD47+/+ DST than mice which received CD47-/- DST. Immunohistochemistry showed an increased heart grafts infiltration of Treg cells in the recipients with CD47-/- DST, but not CD47+/+ DST. Supporting this, we found that donor T-cell proliferation was significantly suppressed in mice which received CD47+/+ DST compared to mice which received CD47-/- DST. There was no difference of inhibitory function of Treg cells between these two groups. CONCLUSION Our results indicated that CD47 expression on DST cells plays an important role in the induction of immune tolerance in mice with skin-heart transplantation. Increased percentage of Treg cells may contribute to immune tolerance induced by CD47+/+ DST.
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Affiliation(s)
- Yu Hu
- Department of Pathology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Honglan Zhou
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Baoshan Gao
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Gang Wang
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Yuantao Wang
- Department of Urology, The First Hospital of Jilin University, Changchun, China
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17
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Tumor cure by radiation therapy and checkpoint inhibitors depends on pre-existing immunity. Sci Rep 2018; 8:7012. [PMID: 29725089 PMCID: PMC5934473 DOI: 10.1038/s41598-018-25482-w] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 04/20/2018] [Indexed: 11/25/2022] Open
Abstract
Radiation therapy is a source of tumor antigen release that has the potential to serve as an endogenous tumor vaccination event. In preclinical models radiation therapy synergizes with checkpoint inhibitors to cure tumors via CD8 T cell responses. To evaluate the immune response initiated by radiation therapy, we used a range of approaches to block the pre-existing immune response artifact initiated by tumor implantation. We demonstrate that blocking immune responses at tumor implantation blocks development of a tumor-resident antigen specific T cell population and prevents tumor cure by radiation therapy combined with checkpoint immunotherapy. These data demonstrate that this treatment combination relies on a pre-existing immune response to cure tumors, and may not be a solution for patients without pre-existing immunity.
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18
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Abstract
Over the past century, solid organ transplantation has been improved both at a surgical and postoperative level. However, despite the improvement in efficiency, safety, and survival, we are still far from obtaining full acceptance of all kinds of allograft in the absence of concomitant treatments. Today, transplanted patients are treated with immunosuppressive drugs (IS) to minimize immunological response in order to prevent graft rejection. Nevertheless, the lack of specificity of IS leads to an increase in the risk of cancer and infections. At this point, cell therapies have been shown as a novel promising resource to minimize the use of IS in transplantation. The main strength of cell therapy is the opportunity to generate allograft-specific tolerance, promoting in this way long-term allograft survival. Among several other regulatory cell types, tolerogenic monocyte-derived dendritic cells (Tol-MoDCs) appear to be an interesting candidate for cell therapy due to their ability to perform specific antigen presentation and to polarize immune response to immunotolerance. In this review, we describe the characteristics and the mechanisms of action of both human Tol-MoDCs and rodent tolerogenic bone marrow-derived DCs (Tol-BMDCs). Furthermore, studies performed in transplantation models in rodents and non-human primates corroborate the potential of Tol-BMDCs for immunoregulation. In consequence, Tol-MoDCs have been recently evaluated in sundry clinical trials in autoimmune diseases and shown to be safe. In addition to autoimmune diseases clinical trials, Tol-MoDC is currently used in the first phase I/II clinical trials in transplantation. Translation of Tol-MoDCs to clinical application in transplantation will also be discussed in this review.
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Affiliation(s)
- Eros Marín
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Nephrologie (ITUN), CHU Nantes, Nantes, France
| | - Maria Cristina Cuturi
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Nephrologie (ITUN), CHU Nantes, Nantes, France
| | - Aurélie Moreau
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Nephrologie (ITUN), CHU Nantes, Nantes, France
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19
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Nelsen MK, Beard KS, Plenter RJ, Kedl RM, Clambey ET, Gill RG. Disruption of Transplant Tolerance by an "Incognito" Form of CD8 T Cell-Dependent Memory. Am J Transplant 2017; 17:1742-1753. [PMID: 28066981 PMCID: PMC5489385 DOI: 10.1111/ajt.14194] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 12/27/2016] [Accepted: 12/29/2016] [Indexed: 01/25/2023]
Abstract
Several approaches successfully achieve allograft tolerance in preclinical models but are challenging to translate into clinical practice. Many clinically relevant factors can attenuate allograft tolerance induction, including intrinsic genetic resistance, peritransplant infection, inflammation, and preexisting antidonor immunity. The prevailing view for immune memory as a tolerance barrier is that the host harbors memory cells that spontaneously cross-react to donor MHC antigens. Such preexisting "heterologous" memory cells have direct reactivity to donor cells and resist most tolerance regimens. In this study, we developed a model system to determine if an alternative form of immune memory could also block tolerance. We posited that host memory T cells could potentially respond to donor-derived non-MHC antigens, such as latent viral antigens or autoantigens, to which the host is immune. Results show that immunity to a model nonself antigen, ovalbumin (OVA), can dramatically disrupt tolerance despite undetectable initial reactivity to donor MHC antigens. Importantly, this blockade of tolerance was CD8+ T cell-dependent and required linked antigen presentation of alloantigens with the test OVA antigen. As such, this pathway represents an unapparent, or "incognito," form of immunity that is sufficient to prevent tolerance and that can be an unforeseen additional immune barrier to clinical transplant tolerance.
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Affiliation(s)
- M. K. Nelsen
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - K. S. Beard
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - R. J. Plenter
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - R. M. Kedl
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - E. T. Clambey
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - R. G. Gill
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO
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20
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Potiron N, Chagneau C, Boeffard F, Soulillou JP, Anegon I, Le Mauff B. Adenovirus-Mediated CTLA4Ig or CD40Ig Gene Transfer Delays Pancreatic Islet Rejection in a Rat-to-Mouse Xenotransplantation Model after Systemic but Not Local Expression. Cell Transplant 2017; 14:263-75. [PMID: 16052908 DOI: 10.3727/000000005783983052] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Transient costimulation signal blockade of either CD28/CD80–86 interactions and/or CD40/CD154 interactions can prevent islet rejection in some models of both allo- and xenotransplantation. We have used adenoviruses coding for CTLA4Ig or CD40Ig and compared the efficacy of genetic modification of islets to systemic production through either intramuscular (IM) or intravenous (IV) injection of these vectors in a rat-to-mouse islet transplantation model. When gene transfer was performed into islets, a high level of primary nonfunction was induced. Furthermore, transduced functional grafts were rejected with the same kinetics as nontransduced islets. In contrast, IM AdCTLA4Ig and IV AdCD40Ig significantly delayed rejection (mean survival time of 54 ± 26.9 and 67.6 ± 44.9 days, respectively, vs. 24.3 ± 9.7 days for unmodified islets, p < 0.05). Combination of ex vivo AdCTLA4Ig islet transduction and IV AdCD40Ig did not improve graft survival further. In conclusion, islet graft transduction with adenoviruses coding for costimulation inhibitors resulted in local expression with low serum concentrations of CTLA4Ig or CD40Ig and was unable to protect islet xenografts from rejection. In contrast, IM or IV gene transfer resulted in high serum concentrations of these molecules and was highly efficient in prolonging xenograft survival. These results contrast with the efficacy of AdCTLA4Ig we observed in a rat islet allotransplantation model and suggest that islet xenograft rejection might be more difficult to control.
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Affiliation(s)
- Nicolas Potiron
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR643, Centre Hospitalo-Universitaire, 30 boulevard Jean Monnet, 44093 Nantes 01, France
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21
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Rossini AA, Parker DC, Phillips NE, Durie FH, Noelle RJ, Mordes JP, Greiner DL. Induction of Immunological Tolerance to Islet Allografts. Cell Transplant 2017; 5:49-52. [PMID: 8665076 DOI: 10.1177/096368979600500109] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
T-cell dependent activation of resting B cells involves the interaction of gp39 on T cells with its receptor, CD40, on B cells. We administered either a combination of T-cell-depleted splenic lymphocytes and anti-gp39 monoclonal antibody or antibody alone to establish islet allografts in mice without continuous immunosuppression. Fully allogeneic H-2q FVB islets were permanently accepted by chemically diabetic H-2b C57BL/6 mice provided that the recipients were pretreated with both T-cell-depleted donor spleen cells and anti-gp39 antibody. Antibody alone was less effective in prolonging allograft survival, but we did observe that anti-gp39 mAb alone can exert an independent, primary effect on islet allograft survival that was dose dependent. Targeting gp39, in combination with lymphocyte transfusion, might prove suitable for tolerance induction and allotransplantation without immunosuppression.
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Affiliation(s)
- A A Rossini
- Department of Medicine, University of Massachusetts Medical School, Worcester 01655, USA
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22
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Foy TM, McIlraith M, Masters SR, Dunn JJ, Rossini AA, Shultz LD, Hesselton RA, Wagar EJ, Lipsky PE, Noelle RJ, Greiner DL. Blockade of Cd40-Cd154 Interferes with Human T cell Engraftment in Scid Mice. Cell Transplant 2017; 7:25-35. [PMID: 9489760 DOI: 10.1177/096368979800700105] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Antibodies to the ligand for CD40 (CD154) have been shown to exert profound effects on the development of cell-mediated immune responses in mice. The present study shows that an antibody to human CD154 (hCD40L) inhibits in vivo Tetanus toxoid (TT) specific secondary antibody responses in hu-PBL-scid mice, as well as the expansion of xenoreactive human T cells in the scid mice. A possible cause for the reduced expansion of xenoreactive, human T cells, was the decreased expression of murine B7.1 and B7.2 caused by the administration of anti-hCD40L. Therefore, it may be that defective maturation of murine antigen-presenting cells impeded the priming and expansion of human xenoreactive T cells.
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Affiliation(s)
- T M Foy
- Department of Microbiology, Dartmouth Medical School, Lebanon, NH 03756, USA
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23
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Regulatory immune cells and functions in autoimmunity and transplantation immunology. Autoimmun Rev 2017; 16:435-444. [DOI: 10.1016/j.autrev.2017.03.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 01/26/2017] [Indexed: 12/15/2022]
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24
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Guzman-Genuino RM, Diener KR. Regulatory B Cells in Pregnancy: Lessons from Autoimmunity, Graft Tolerance, and Cancer. Front Immunol 2017; 8:172. [PMID: 28261223 PMCID: PMC5313489 DOI: 10.3389/fimmu.2017.00172] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 02/03/2017] [Indexed: 12/26/2022] Open
Abstract
The success of pregnancy is contingent on the maternal immune system recognizing and accommodating a growing semi-allogeneic fetus. Specialized subsets of lymphocytes capable of negative regulation are fundamental in this process, and include the regulatory T cells (Tregs) and potentially, regulatory B cells (Bregs). Most of our current understanding of the immune regulatory role of Bregs comes from studies in the fields of autoimmunity, transplantation tolerance, and cancer biology. Bregs control autoimmune diseases and can elicit graft tolerance by inhibiting the differentiation of effector T cells and dendritic cells (DCs), and activating Tregs. Furthermore, in cancer, Bregs are hijacked by neoplastic cells to promote tumorigenesis. Pregnancy therefore represents a condition that reconciles these fields-mechanisms must be in place to ensure maternal immunological tolerance throughout gravidity to allow the semi-allogeneic fetus to grow within. Thus, the mechanisms underlying Breg activities in autoimmune diseases, transplantation tolerance, and cancer may take place during pregnancy as well. In this review, we discuss the potential role of Bregs as guardians of pregnancy and propose an endocrine-modulated feedback loop highlighting the Breg-Treg-tolerogenic DC interface essential for the induction of maternal immune tolerance.
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Affiliation(s)
- Ruth Marian Guzman-Genuino
- Experimental Therapeutics Laboratory, School of Pharmacy and Medical Science, Hanson Institute and Sansom Institute for Health Research, University of South Australia , Adelaide, SA , Australia
| | - Kerrilyn R Diener
- Experimental Therapeutics Laboratory, School of Pharmacy and Medical Science, Hanson Institute and Sansom Institute for Health Research, University of South Australia, Adelaide, SA, Australia; Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
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25
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Lin CH, Wang YL, Anggelia MR, Chuang WY, Cheng HY, Mao Q, Zelken JA, Lin CH, Zheng XX, Lee WPA, Brandacher G. Combined Anti-CD154/CTLA4Ig Costimulation Blockade-Based Therapy Induces Donor-Specific Tolerance to Vascularized Osteomyocutaneous Allografts. Am J Transplant 2016; 16:2030-2041. [PMID: 26914847 DOI: 10.1111/ajt.13694] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 12/06/2015] [Accepted: 12/20/2015] [Indexed: 01/25/2023]
Abstract
Tolerance induction by means of costimulation blockade has been successfully applied in solid organ transplantation; however, its efficacy in vascularized composite allotransplantation, containing a vascularized bone marrow component and thus a constant source of donor-derived stem cells, remains poorly explored. In this study, osteomyocutaneous allografts (alloOMCs) from Balb/c (H2(d) ) mice were transplanted into C57BL/6 (H2(b) ) recipients. Immunosuppression consisted of 1 mg anti-CD154 on day 0, 0.5 mg CTLA4Ig on day 2 and rapamycin (RPM; 3 mg/kg per day from days 0-7, then every other day for 3 weeks). Long-term allograft survival, donor-specific tolerance and donor-recipient cell trafficking were evaluated. Treatment with costimulation blockade plus RPM resulted in long-term graft survival (>120 days) of alloOMC in 12 of 15 recipients compared with untreated controls (median survival time [MST] ≈10.2 ± 0.8 days), RPM alone (MST ≈33 ± 5.5 days) and costimulation blockade alone (MST ≈45.8 ± 7.1 days). Donor-specific hyporesponsiveness in recipients with viable grafts was demonstrated in vitro. Evidence of donor-specific tolerance was further assessed in vivo by secondary donor-specific skin graft survival and third-party graft rejection. A significant increase of Foxp3(+) regulatory T cells was evident in tolerant animals. Donor cells populated peripheral blood, thymus, and both donor and recipient bone marrow. Consequently, combined anti-CD154/CTLA4Ig costimulation blockade-based therapy induces donor-specific tolerance in a stringent murine alloOMC transplant model.
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Affiliation(s)
- C H Lin
- Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Y L Wang
- Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - M R Anggelia
- Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - W Y Chuang
- Department of Pathology, Chang Gung Memorial Hospital, Chang Gung Medical College and Chang Gung University, Taoyuan, Taiwan
| | - H Y Cheng
- Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Q Mao
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD
| | - J A Zelken
- Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - C H Lin
- Center for Vascularized Composite Allotransplantation, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, and School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - X X Zheng
- Research Center of Translational Medicine, Shanghai East Hospital, Tongji University, Shanghai, China
| | - W P A Lee
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD
| | - G Brandacher
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD
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26
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Tseng M, Ge S, Roberts R, Kuo C, Choi J, Nissen NN, Kim I, Chu M, Shin B, Toyoda M, Jordan SC. Liver Transplantation in a Patient With CD40 Ligand Deficiency and Hyper-IgM Syndrome: Clinical and Immunological Assessments. Am J Transplant 2016; 16:1626-1632. [PMID: 26762604 DOI: 10.1111/ajt.13580] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 09/11/2015] [Accepted: 10/05/2015] [Indexed: 01/26/2023]
Abstract
Monoclonal antibodies that disrupt CD40-CD40 ligand (CD40L) interactions are likely to have use in human transplantation. However, the extent of the immunosuppressive effects of CD40-CD40L blockade in humans is unknown. Hyper-IgM syndrome (HIGM) is a rare primary immunodeficiency syndrome characterized by defects in the CD40-CD40L pathway, severe immune deficiency (IgG), and high or normal IgM levels. However, the effects of CD40L deficiency on T- and natural killer (NK)-cell function is not established. Here, we present a patient with HIGM syndrome who underwent liver transplantation for hepatitis C virus infection. Posttransplantation, NK-cell antibody-dependent cytokine release (γ-interferon) to alloantigens and T cell responses to viral antigens and mitogens were assessed and showed normal CD4+ , CD8+ , and NK-cell responses. We also examined antibody-dependent cellular cytotoxicity against a CD40+ and HLA-expressing cell line. These experiments confirmed that the patient's NK cells were equivalent to those of normal subjects in mediating antibody-dependent cellular cytotoxicity despite the absence of CD40-CD40L interactions. Mitogenic stimulation of the patient's peripheral blood mononuclear cells showed no expression of CD40L on T and NK cells compared with increased expression in normal subjects. Taken together, these data suggest that absence of CD40L expression is responsible for aberrant B cell immunity but had little impact on NK- and T cell immune responses in vitro.
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Affiliation(s)
- M Tseng
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | - S Ge
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
| | - R Roberts
- Department of Pediatrics, Division of Immunology, UCLA Center for the Health Sciences, Los Angeles, CA
| | - C Kuo
- Department of Pediatrics, Division of Immunology, UCLA Center for the Health Sciences, Los Angeles, CA
| | - J Choi
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | - N N Nissen
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | - I Kim
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | - M Chu
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
| | - B Shin
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
| | - M Toyoda
- Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
| | - S C Jordan
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA.,Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
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27
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Mechanisms of immunological tolerance. Clin Biochem 2016; 49:324-8. [DOI: 10.1016/j.clinbiochem.2015.05.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 05/11/2015] [Accepted: 05/17/2015] [Indexed: 02/06/2023]
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28
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Jurczyk A, Nowosielska A, Przewozniak N, Aryee KE, DiIorio P, Blodgett D, Yang C, Campbell-Thompson M, Atkinson M, Shultz L, Rittenhouse A, Harlan D, Greiner D, Bortell R. Beyond the brain: disrupted in schizophrenia 1 regulates pancreatic β-cell function via glycogen synthase kinase-3β. FASEB J 2016; 30:983-93. [PMID: 26546129 PMCID: PMC4714549 DOI: 10.1096/fj.15-279810] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 10/28/2015] [Indexed: 12/20/2022]
Abstract
Individuals with schizophrenia and their first-degree relatives have higher rates of type 2 diabetes (T2D) than the general population (18-30 vs. 1.2-6.3%), independent of body mass index and antipsychotic medication, suggesting shared genetic components may contribute to both diseases. The cause of this association remains unknown. Mutations in disrupted in schizophrenia 1 (DISC1) increase the risk of developing psychiatric disorders [logarithm (base 10) of odds = 7.1]. Here, we identified DISC1 as a major player controlling pancreatic β-cell proliferation and insulin secretion via regulation of glycogen synthase kinase-3β (GSK3β). DISC1 expression was enriched in developing mouse and human pancreas and adult β- and ductal cells. Loss of DISC1 function, through siRNA-mediated depletion or expression of a dominant-negative truncation that models the chromosomal translocation of human DISC1 in schizophrenia, resulted in decreased β-cell proliferation (3 vs. 1%; P < 0.01), increased apoptosis (0.1 vs. 0.6%; P < 0.01), and glucose intolerance in transgenic mice. Insulin secretion was reduced (0.5 vs. 0.1 ng/ml; P < 0.05), and critical β-cell transcription factors Pdx1 and Nkx6.1 were significantly decreased. Impaired DISC1 allowed inappropriate activation of GSK3β in β cells, and antagonizing GSK3β (SB216763; IC50 = 34.3 nM) rescued the β-cell defects. These results uncover an unexpected role for DISC1 in normal β-cell physiology and suggest that DISC1 dysregulation contributes to T2D independently of its importance for cognition.
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Affiliation(s)
- Agata Jurczyk
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - Anetta Nowosielska
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - Natalia Przewozniak
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - Ken-Edwin Aryee
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - Philip DiIorio
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - David Blodgett
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - Chaoxing Yang
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - Martha Campbell-Thompson
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - Mark Atkinson
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - Leonard Shultz
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - Ann Rittenhouse
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - David Harlan
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - Dale Greiner
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
| | - Rita Bortell
- *Diabetes Center of Excellence, Program in Molecular Medicine, and Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts, USA; Department of Public Health, University of Massachusetts, Amherst, Massachusetts, USA; Department of Pathology, University of Florida, Gainesville, Florida, USA; and The Jackson Laboratory; Bar Harbor, Maine, USA
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29
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Durand J, Chiffoleau E. B cells with regulatory properties in transplantation tolerance. World J Transplant 2015; 5:196-208. [PMID: 26722647 PMCID: PMC4689930 DOI: 10.5500/wjt.v5.i4.196] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 08/19/2015] [Accepted: 09/30/2015] [Indexed: 02/05/2023] Open
Abstract
Induction of tolerance remains a major goal in transplantation. Indeed, despite potent immunosuppression, chronic rejection is still a real problem in transplantation. The humoral response is an important mediator of chronic rejection, and numerous strategies have been developed to target either B cells or plasma cells. However, the use of anti-CD20 therapy has highlighted the beneficial role of subpopulation of B cells, termed regulatory B cells. These cells have been characterized mainly in mice models of auto-immune diseases but emerging literature suggests their role in graft tolerance in transplantation. Regulatory B cells seem to be induced following inflammation to restrain excessive response. Different phenotypes of regulatory B cells have been described and are functional at various differentiation steps from immature to plasma cells. These cells act by multiple mechanisms such as secretion of immuno-suppressive cytokines interleukin-10 (IL-10) or IL-35, cytotoxicity, expression of inhibitory receptors or by secretion of non-inflammatory antibodies. Better characterization of the development, phenotype and mode of action of these cells seems urgent to develop novel approaches to manipulate the different B cell subsets and the response to the graft in a clinical setting.
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30
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Lymph Node Stromal Fiber ER-TR7 Modulates CD4+ T Cell Lymph Node Trafficking and Transplant Tolerance. Transplantation 2015; 99:1119-25. [PMID: 25769074 DOI: 10.1097/tp.0000000000000664] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Trafficking and differentiation of naive CD4+ and regulatory T cells (Treg) within the lymph node (LN) are integral for tolerance induction. The LN is comprised of stromal fibers that dictate lymphocyte migration and LN structure, organization, and microanatomic domains. Distribution of the stromal fiber ER-TR7 changes within the LN after antigenic challenge, but the contributions of ER-TR7 to the resulting immune response remain undefined. We hypothesized that these stromal fiber structural changes affect T cell fate and subsequently allograft survival. METHODS C57BL/6 mice were left naive (untreated) or made immune or tolerant (donor-specific BALB/c splenocyte transfusion -/+ anti-CD40L monoclonal antibody), or made tolerant and received anti-ER-TR7 monoclonal antibody. Donor-specific T-cell migration was visualized by adoptive transfer of carboxyfluorescein diacetate, succinimidyl ester-labeled TEa T cell receptor transgenic CD4+ cells. Immunohistochemistry was performed on LNs to detect stromal fiber distribution, structure, CCL21 presence, and Treg and donor-specific cell location relative to high endothelial venules (HEV). Naive, tolerant, and tolerant + anti-ER-TR7 mice received BALB/c heterotopic cardiac allografts and graft survival was monitored. RESULTS The ER-TR7 distribution changed after the induction of tolerance vs. immunity. Treating tolerant mice with anti-ER-TR7 altered HEV basement membrane structure and the distribution of CCL21 within the LN. These differences were mirrored by changes in the migration of naive and Treg cells within and surrounding the HEV. Anti-ER-TR7 prevented tolerance induction and resulted in allograft inflammation and rejection. CONCLUSIONS These results identify ER-TR7 as an important component of LN structure in tolerance and a direct target for immune modulation.
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31
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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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32
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Graca L. Transplantation tolerance: context matters. Eur J Immunol 2015; 45:1921-5. [PMID: 26031651 DOI: 10.1002/eji.201545762] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 05/13/2015] [Accepted: 05/27/2015] [Indexed: 11/07/2022]
Abstract
Costimulation blockade has been one of the most studied strategies to achieve immune tolerance, particularly in transplantation. Yet, in spite of the robust nature of the tolerance-inducing potential of costimulation blockade, a comprehensive understanding of the molecular and cellular mechanisms underlying tolerance induction is still missing. Nevertheless, progress has been continuously made. In this issue of the European Journal of Immunology, Chai et al. [Eur. J. Immunol. 2015. 45: 2017-2027] show that transplantation tolerance induced with an anti-CD154 monoclonal antibody relies on the coexistence of several tolerogenic mechanisms rather than one simple regulatory mechanism. These observations highlight the importance of concerted actions involving multiple pathways, namely apoptosis, acquisition of regulatory cells, or inhibition of proliferation, all of which contribute to the induction and maintenance of robust immune tolerance. A better understanding of these distinct tolerogenic pathways may lead to the development of better tolerance-inducing therapeutics.
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Affiliation(s)
- Luis Graca
- Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.,Instituto Gulbenkian de Ciências, Oeiras, Portugal
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33
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Chai JG, Ratnasothy K, Bucy RP, Noelle RJ, Lechler R, Lombardi G. Allospecific CD4(+) T cells retain effector function and are actively regulated by Treg cells in the context of transplantation tolerance. Eur J Immunol 2015; 45:2017-27. [PMID: 25944401 DOI: 10.1002/eji.201545455] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 03/12/2015] [Accepted: 04/30/2015] [Indexed: 01/31/2023]
Abstract
Although donor-specific transfusion (DST) plus CD154 blockade represents a robust protocol for inducing transplantation tolerance, the underlying mechanisms are incompletely understood. In a murine T-cell adoptive transfer model, we have visualized alloantigen-specific, TCR-transgenic for H2-A(b) /H2-K(d) 54-68 epitope (TCR75) CD4(+) T cells with indirect allospecificity during the course of tolerance induction. Three main observations were made. First, although the majority of TCR75 CD4(+) T cells were deleted following DST plus CD154 blockade, the surviving TCR75 CD4(+) T cells were capable of making IL-2, upregulating CD44, and undergoing cell division, suggesting that they were functionally active. Indeed, residual TCR75 CD4(+) T cells reisolated from the primary recipients given DST plus CD154 blockade were fully capable of rejecting allografts upon secondary transfer. Second, in tolerant mice, TCR75 CD4(+) T cells were not induced to express Foxp3 in the graft-draining lymph node. TCR75 CD4(+) T cells were also absent in accepted graft tissues in which endogenous Treg cells were enriched. Finally, DST plus CD154 blockade resulted in an abortive expansion of TCR75 CD4(+) T cells, a process that required the presence of endogenous Treg cells. Collectively, surviving TCR75 CD4(+) T cells are immunocompetent but kept in check by an endogenous immunosuppressive network induced by DST plus CD154 blockade.
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Affiliation(s)
- Jian-Guo Chai
- MRC Centre for Transplantation, King's College London, London, UK.,Therapeutic Immunology Group, Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | | | - R Pat Bucy
- Department of Pathology, University of Alabama, Birmingham, AL, USA
| | - Randolph J Noelle
- MRC Centre for Transplantation, King's College London, London, UK.,Department of Microbiology and Immunology, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, NH, USA
| | - Robert Lechler
- MRC Centre for Transplantation, King's College London, London, UK
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34
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Ferrer IR, Hester J, Bushell A, Wood KJ. Induction of transplantation tolerance through regulatory cells: from mice to men. Immunol Rev 2015; 258:102-16. [PMID: 24517428 DOI: 10.1111/imr.12158] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Organ transplantation results in the activation of both innate and adaptive immune responses to the foreign antigens. While these responses can be limited with the use of systemic immunosuppressants, the induction of regulatory cell populations may be a novel strategy for the maintenance of specific immunological unresponsiveness that can reduce the severity of the detrimental side effects of current therapies. Our group has extensively researched different regulatory T-cell induction protocols for use as cellular therapy in transplantation. In this review, we address the cellular and molecular mechanisms behind regulatory T-cell suppression and their stability following induction protocols. We further discuss the use of different hematopoietically derived regulatory cell populations, including regulatory B cells, regulatory macrophages, tolerogenic dendritic cells, and myeloid-derived suppressor cells, for the induction of transplantation tolerance in light of new clinical trials developing therapies with some of these populations.
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Affiliation(s)
- Ivana R Ferrer
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK
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35
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Zhang Q, Ichimaru N, Higuchi S, Cai S, Hou J, Fujino M, Nonomura N, Kobayashi M, Ando H, Uno A, Sakurai K, Mochizuki S, Adachi Y, Ohno N, Zou H, Xu J, Li XK, Takahara S. Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system. Gene Ther 2015; 22:217-26. [DOI: 10.1038/gt.2014.119] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 11/06/2014] [Accepted: 11/17/2014] [Indexed: 01/27/2023]
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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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Song L, Ma A, Dun H, Hu Y, Zeng L, Bai J, Zhang G, Kinugasa F, Sudo Y, Miyao Y, Okimura K, Miura T, Daloze P, Chen H. Effects of ASKP1240 combined with tacrolimus or mycophenolate mofetil on renal allograft survival in Cynomolgus monkeys. Transplantation 2014; 98:267-76. [PMID: 24992357 PMCID: PMC4175122 DOI: 10.1097/tp.0000000000000236] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 04/04/2014] [Indexed: 01/22/2023]
Abstract
BACKGROUND Blocking the CD40-CD154 signal pathway has previously shown promise as a strategy to prevent allograft rejection. In this study, the efficacy of a novel fully human anti-CD40 monoclonal antibody-ASKP1240, administered as a monotherapy or combination therapy (subtherapeutic dose of tacrolimus or mycophenolate mofetil), on the prevention of renal allograft rejection was evaluated in Cynomolgus monkeys. METHODS Heterotopic kidney transplants were performed in ABO-compatible, stimulation index 2.5 or higher in the two-way mixed lymphocyte reaction monkey pairs. Animals were divided into 12 groups and observed for a maximum of 180 days. Histopathologic, hematology, and biochemistry analyses were conducted in all groups. Cytokine release (interleukin [IL]-2, IL-4, IL-5, IL-6, tumor necrosis factor, and interferon-γ) was investigated in several groups. RESULTS ASKP1240 prolonged renal allograft survival in a dose-dependent manner in monotherapy. Low-dose (2 mg/kg) or high-dose (5 mg/kg) ASKP1240, in combination with mycophenolate mofetil (15 mg/kg) or tacrolimus (1 mg/kg), showed a significantly longer allograft survival time compared with monotherapy groups. No obvious side effects including drug-related thromboembolic complications were found. Cytokine release was not induced by ASKP1240 administration. CONCLUSION The present study indicates that ASKP1240, alone or in combination with other immunosuppressive drugs, could be a promising antirejection agent in organ transplantation.
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Affiliation(s)
- Lijun Song
- 1 Department of Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada. 2 Laboratory Animals Center, the Academy of Military Medical Sciences, Beijing, China. 3 Translational and Development Pharmacology-US, Drug Discovery Research, Astellas Research Institute of America LLC, Northbrook, IL. 4 Astellas Research Technology Inc., Osaka, Japan. 5 Drug Metabolism Research Labs. Astellas Pharma Inc., Osaka, Japan. 6 Pharmacological Research Labs., Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan. 7 Address correspondence to: Huifang Chen, M.D., Ph.D., Laboratory of Experimental Surgery, Research Center, CHUM, Notre-Dame Hospital, University of Montréal, 2099 Alexandre de Sève, Montréal, Room Y1611, Québec, Canada H2L 2W5
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Warren KJ, Iwami D, Harris DG, Bromberg JS, Burrell BE. Laminins affect T cell trafficking and allograft fate. J Clin Invest 2014; 124:2204-18. [PMID: 24691446 DOI: 10.1172/jci73683] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 01/23/2014] [Indexed: 01/01/2023] Open
Abstract
Lymph nodes (LNs) are integral sites for the generation of immune tolerance, migration of CD4⁺ T cells, and induction of Tregs. Despite the importance of LNs in regulation of inflammatory responses, the LN-specific factors that regulate T cell migration and the precise LN structural domains in which differentiation occurs remain undefined. Using intravital and fluorescent microscopy, we found that alloreactive T cells traffic distinctly into the tolerant LN and colocalize in exclusive regions with alloantigen-presenting cells, a process required for Treg induction. Extracellular matrix proteins, including those of the laminin family, formed regions within the LN that were permissive for colocalization of alloantigen-presenting cells, alloreactive T cells, and Tregs. We identified unique expression patterns of laminin proteins in high endothelial venule basement membranes and the cortical ridge that correlated with alloantigen-specific immunity or immune tolerance. The ratio of laminin α4 to laminin α5 was greater in domains within tolerant LNs, compared with immune LNs, and blocking laminin α4 function or inducing laminin α5 overexpression disrupted T cell and DC localization and transmigration through tolerant LNs. Furthermore, reducing α4 laminin circumvented tolerance induction and induced cardiac allograft inflammation and rejection in murine models. This work identifies laminins as potential targets for immune modulation.
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Abstract
We are entering an exciting time in the study of immunologic tolerance. Several cellular and molecular strategies have been developed that show promise in nonhuman transplant models and these approaches are just now appearing in clinical trials. Tolerance strategies that prevent immune rejection and obviate the need for immunosuppressive medications (with inherent risk of cancer, infection, and organ toxicity) would improve both graft and patient survival. Each tolerance protocol brings its own set of associated risks. As the results of these trials become available, we must continue to evaluate their successes and failures. The balance of these outcomes will help us answer the question: "Tolerance-Is it worth it?"
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Affiliation(s)
- Erik B Finger
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455
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El-Charabaty E, Geara AS, Ting C, El-Sayegh S, Azzi J. Belatacept: a new era of immunosuppression? Expert Rev Clin Immunol 2014; 8:527-36. [DOI: 10.1586/eci.12.42] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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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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Chesneau M, Michel L, Degauque N, Brouard S. Regulatory B cells and tolerance in transplantation: from animal models to human. Front Immunol 2013; 4:497. [PMID: 24427159 PMCID: PMC3876023 DOI: 10.3389/fimmu.2013.00497] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 12/17/2013] [Indexed: 12/23/2022] Open
Abstract
Until recently, the role of B cells in transplantation was thought to be restricted to producing antibodies that have been clearly shown to be deleterious in the long-term, but, in fact, B cells are also able to produce cytokine and to present antigen. Their role as regulatory cells in various pathological situations has also been highlighted, and their role in transplantation is beginning to emerge in animal, and also in human, models. This review summarizes the different studies in animals and humans that suggest a B-cell regulatory role in the transplant tolerance mechanisms.
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Affiliation(s)
- Mélanie Chesneau
- Institut National de la Santé et de la Recherche Médicale U1064, Institut de Transplantation Urologie Néphrologie , Nantes , France ; Université de Nantes , Nantes , France
| | - Laure Michel
- Institut National de la Santé et de la Recherche Médicale U1064, Institut de Transplantation Urologie Néphrologie , Nantes , France ; Centre Hospitalier Universitaire , Nantes , France
| | - Nicolas Degauque
- Institut National de la Santé et de la Recherche Médicale U1064, Institut de Transplantation Urologie Néphrologie , Nantes , France
| | - Sophie Brouard
- Institut National de la Santé et de la Recherche Médicale U1064, Institut de Transplantation Urologie Néphrologie , Nantes , France ; Université de Nantes , Nantes , France ; Centre Hospitalier Universitaire , Nantes , France
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Larocca RA, Moraes-Vieira PM, Bassi ÊJ, Semedo P, de Almeida DC, da Silva MB, Thornley T, Pacheco-Silva A, Câmara NOS. Adipose tissue-derived mesenchymal stem cells increase skin allograft survival and inhibit Th-17 immune response. PLoS One 2013; 8:e76396. [PMID: 24124557 PMCID: PMC3790669 DOI: 10.1371/journal.pone.0076396] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 08/29/2013] [Indexed: 12/29/2022] Open
Abstract
Adipose tissue-derived mesenchymal stem cells (ADSC) exhibit immunosuppressive capabilities both in vitro and in vivo. Their use for therapy in the transplant field is attractive as they could render the use of immunosuppressive drugs unnecessary. The aim of this study was to investigate the effect of ADSC therapy on prolonging skin allograft survival. Animals that were treated with a single injection of donor allogeneic ADSC one day after transplantation showed an increase in donor skin graft survival by approximately one week. This improvement was associated with preserved histological morphology, an expansion of CD4(+) regulatory T cells (Treg) in draining lymph nodes, as well as heightened IL-10 expression and down-regulated IL-17 expression. In vitro, ADSC inhibit naïve CD4(+) T cell proliferation and constrain Th-1 and Th-17 polarization. In summary, infusion of ADSC one day post-transplantation dramatically increases skin allograft survival by inhibiting the Th-17 pathogenic immune response and enhancing the protective Treg immune response. Finally, these data suggest that ADSC therapy will open new opportunities for promoting drug-free allograft survival in clinical transplantation.
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Affiliation(s)
- Rafael Assumpção Larocca
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute for Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Harvard Medical School, Department of Medicine, The Transplant Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
- * E-mail:
| | - Pedro Manoel Moraes-Vieira
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute for Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Harvard Medical School, Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
| | - Ênio José Bassi
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute for Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Patrícia Semedo
- Laboratory of Clinical and Experimental Immunology, Division of Nephrology, Federal University of São Paulo, São Paulo, Brazil
| | - Danilo Candido de Almeida
- Laboratory of Clinical and Experimental Immunology, Division of Nephrology, Federal University of São Paulo, São Paulo, Brazil
| | - Marina Burgos da Silva
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute for Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Thomas Thornley
- Harvard Medical School, Department of Medicine, The Transplant Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
| | - Alvaro Pacheco-Silva
- Laboratory of Clinical and Experimental Immunology, Division of Nephrology, Federal University of São Paulo, São Paulo, Brazil
- Instituto Israelita de Ensino e Pesquisa Albert Einstein Hospital, Renal Transplantation Division, São Paulo, Brazil
| | - Niels Olsen Saraiva Câmara
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute for Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Laboratory of Clinical and Experimental Immunology, Division of Nephrology, Federal University of São Paulo, São Paulo, Brazil
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Murray SE, Toren KG, Parker DC. Peripheral CD4(+) T-cell tolerance is induced in vivo by rare antigen-bearing B cells in follicular, marginal zone, and B-1 subsets. Eur J Immunol 2013; 43:1818-27. [PMID: 23532986 DOI: 10.1002/eji.201242784] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2012] [Revised: 02/25/2013] [Accepted: 03/20/2013] [Indexed: 01/30/2023]
Abstract
B cells are efficient APCs when they internalize antigen via BCR-mediated uptake. Adoptively transferred antigen-presenting B cells can induce T-cell tolerance to foreign and self antigens; however, it is unknown whether endogenous B cells presenting self-peptides interact with naïve T cells and contribute to peripheral T-cell self-tolerance. Moreover, the relative abilities of mature B-cell subsets to induce T-cell tolerance have not been examined. To address these questions, we created a new mouse model wherein a very small fraction of B cells expresses an antigen transgene that cannot be transferred to other APCs. We limited antigen expression to follicular, marginal zone, or B-1 B-cell subsets and found that small numbers of each subset interacted with naïve antigen-specific T cells. Although antigen expressed by B-1 B cells induced the most T-cell division, divided T cells subsequently disappeared from secondary lymphoid tissues. Independent of which B-cell subset presented antigen, the remaining T cells were rendered hypo-responsive, and this effect was not associated with Foxp3 expression. Our data show that physiologically relevant proportions of B cells can mediate peripheral T-cell tolerance, and suggest that the mechanisms of tolerance induction might differ among follicular, marginal zone, and B-1 B-cell subsets.
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Affiliation(s)
- Susan E Murray
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239, USA.
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45
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Abstract
T cells must be activated before they can elicit damage to allografts, through interaction of their T cell receptor (TCR) with peptide-MHC complex and through accessory molecules. Signaling through accessory molecules or costimulatory molecules is a critical way for the immune system to fine tune T cell activation. An emerging therapeutic strategy is to target selective molecules involved in the process of T cell activation using biologic agents, which do not impact TCR signaling, thus only manipulating the T cells, which recognize alloantigen. Costimulatory receptors and their ligands are attractive targets for this strategy and could be used both to prevent acute graft rejection as well as for maintenance immunosuppression. Therapeutic agents targeting costimulatory molecules, notably belatacept, have made the progression from the bench, through nonhuman primate studies and into the clinic. This overview describes some of the most common costimulatory molecules, their role in T cell activation, and the development of reagents, which target these pathways and their efficacy in transplantation.
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Affiliation(s)
| | | | - Kathryn J Wood
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU UK
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46
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Dave SD, Vanikar A, Trivedi HL, Gumber MR, Patel HV, Shah PR, Kute VB. Stem cells versus donor specific transfusions for tolerance induction in living donor renal transplantation: a single-center experience. Transplantation 2013; 95:155-160. [PMID: 23263505 DOI: 10.1097/tp.0b013e3182752bcc] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND We undertook this study to define the role of stem cell transplantation (SCT) versus donor-specific transfusion (DST) in tolerance induction and sustenance in living donor renal transplantation (LDRT). METHODS In this prospective three-armed trial in LDRT with 13 patients each in demographically well-balanced groups, tolerance induction protocol (TIP) was used with SCT in group 1, DST in group 2, and no induction in group 3. Tolerance induction protocol consisted of SCT/DST under conditioning with bortezomib, methylprednisone, rituximab, and rabbit antithymocyte globulin. Transplantation was performed with prednisone in groups 1 and 2 and with triple immunosuppression in group 3, if lymphocyte/flow crossmatch was negative; and if donor-specific antibodies (DSAs) were absent in the first 2 groups. Posttransplant monitoring included serum creatinine (SCr), peripheral T-regulatory cells (pTregs)(127/CD4+/25), and DSA for groups 1 and 2; DSA was eliminated in group 3. Rescue IS was started with rise of SCr/DSA/ rejection. RESULTS Tolerance induction protocol was safe. Over a mean follow-up of 2 years, no patient/graft was lost in groups 1 and 2. One patient of group 3 lost graft to noncompliance. Protocol biopsies were unremarkable. Rejections were noted in six patients of group 1, five of group 2, and seven of group 3. Donor-specific antibodies were elevated in three patients of both groups. Mean SCr of all groups was similar; however, pTregs were increased posttransplant in groups 1 and 2 versus group 3. Group 1 had sustained rise in pTregs. CONCLUSION Stem cell transplantation and DST are useful for immunosuppression minimization in LDRT with sustained generation of pTregs with SCT.
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Affiliation(s)
- Shruti D Dave
- Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G. R. Doshi and K. M. Mehta Institute of Kidney Diseases and Research Centre (IKDRC)-Dr. H.L. Trivedi Institute of Transplantation Sciences (ITS), Civil Hospital Campus, Asarwa, Ahmedabad, Gujarat, India.
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47
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Wang Y, Wang H, Bronson R, Fu Y, Yang YG. Rapid dendritic cell activation and resistance to allotolerance induction in anti-CD154-treated mice receiving CD47-deficient donor-specific transfusion. Cell Transplant 2013; 23:355-63. [PMID: 23295133 DOI: 10.3727/096368912x661346] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47(+/+) B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST > 150 days). Donor heart survival was improved in anti-CD154-treated BALB/c mice that received CD47(+/-) (MST = 90 days) or CD47(-/-) B6 DST (MST = 42 days) when compared to the nontreated (MST = 7 days) and anti-CD154 alone-treated (MST = 15 days) controls, but significantly reduced when compared to mice receiving anti-CD154 plus CD47(+/+) B6 DST. Recipient mice treated with anti-CD154 plus CD47(-/-) or CD47(+/-) DST also showed significantly increased antidonor, but not anti-third-party, MLR responses compared to those receiving anti-CD154 and CD47(+/+) DST. Furthermore, CD47(-/-) DST induced rapid activation of CD11c(hi)SIRPα(hi)CD8α(-) DCs via a mechanism independent of donor alloantigens. These results demonstrated that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.
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Affiliation(s)
- Yuantao Wang
- First Hospital of Jilin University, Changchun, China
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Lowe M, Badell IR, Thompson P, Martin B, Leopardi F, Strobert E, Price AA, Abdulkerim HS, Wang R, Iwakoshi NN, Adams AB, Kirk AD, Larsen CP, Reimann KA. A novel monoclonal antibody to CD40 prolongs islet allograft survival. Am J Transplant 2012; 12:2079-87. [PMID: 22845909 PMCID: PMC3410651 DOI: 10.1111/j.1600-6143.2012.04054.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The importance of CD40/CD154 costimulatory pathway blockade in immunosuppression strategies is well-documented. Efforts are currently focused on monoclonal antibodies specific for CD40 because of thromboembolic complications associated with monoclonal antibodies directed towards CD154. Here we present the rational development and characterization of a novel antagonistic monoclonal antibody to CD40. Rhesus macaques were treated with the recombinant anti-CD40 mAb, 2C10, or vehicle before immunization with keyhole limpet hemocyanin (KLH). Treatment with 2C10 successfully inhibited T cell-dependent antibody responses to KLH without significant peripheral B cell depletion. Subsequently, MHC-mismatched macaques underwent intraportal allogeneic islet transplantation and received basiliximab and sirolimus with or without 2C10. Islet graft survival was significantly prolonged in recipients receiving 2C10 (graft survival time 304, 296, 265, 163 days) compared to recipients receiving basiliximab and sirolimus alone (graft survival time 8, 8, 10 days). The survival advantage conferred by treatment with 2C10 provides further evidence for the importance of blockade of the CD40/CD154 pathway in preventing alloimmune responses. 2C10 is a particularly attractive candidate for translation given its favorable clinical profile.
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Affiliation(s)
- M Lowe
- Emory Transplant Center, Department of Surgery, Emory University, Atlanta, GA, USA
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Lee KM, Kim JI, Stott R, Soohoo J, O’Connor MR, Yeh H, Zhao G, Eliades P, Fox C, Cheng N, Deng S, Markmann JF. Anti-CD45RB/anti-TIM-1-induced tolerance requires regulatory B cells. Am J Transplant 2012; 12:2072-8. [PMID: 22494812 PMCID: PMC3396747 DOI: 10.1111/j.1600-6143.2012.04055.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The role of B cells in transplant tolerance remains unclear. Although B-cell depletion often prolongs graft survival, sometimes it results in more rapid rejection, suggesting that B cells may have regulatory activity. We previously demonstrated that tolerance induction by anti-CD45RB antibody requires recipient B cells. Here, we show that anti-CD45RB in combination with anti-TIM-1 antibody has a synergistic effect, inducing tolerance in all recipients in a mouse islet allograft model. This effect depends on the presence of recipient B cells, requires B-cell IL-10 activity, and is antigen-specific. These data suggest the existence of a regulatory B-cell population that promotes tolerance via an IL-10-dependent pathway.
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Affiliation(s)
- Kang Mi Lee
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - James I. Kim
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Ryan Stott
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Julie Soohoo
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Matthew R O’Connor
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Heidi Yeh
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Gaoping Zhao
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114,Department of Surgery, Sichuan Provincial People’s Hospital and Sichuan Academy of Medical Sciences, Chengdu 610072, Sichuan Province, P. R. China
| | - Philip Eliades
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Courtney Fox
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Nan Cheng
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Shaoping Deng
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114,Department of Surgery, Sichuan Provincial People’s Hospital and Sichuan Academy of Medical Sciences, Chengdu 610072, Sichuan Province, P. R. China
| | - James F. Markmann
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
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50
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Ferrer IR, Wagener ME, Song M, Ford ML. CD154 blockade alters innate immune cell recruitment and programs alloreactive CD8+ T cells into KLRG-1(high) short-lived effector T cells. PLoS One 2012; 7:e40559. [PMID: 22792369 PMCID: PMC3390379 DOI: 10.1371/journal.pone.0040559] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Accepted: 06/08/2012] [Indexed: 11/19/2022] Open
Abstract
CD154/CD40 blockade combined with donor specific transfusion remains one of the most effective therapies in prolonging allograft survival. Despite this, the mechanisms by which these pathways synergize to prevent rejection are not completely understood. Utilizing a BALB/c (H2-K(d)) to B6 (H2-K(b)) fully allogeneic skin transplant model system, we performed a detailed longitudinal analysis of the kinetics and magnitude of CD8(+) T cell expansion and differentiation in the presence of CD154/CD40 pathway blockade. Results demonstrated that treatment with anti-CD154 vs. DST had distinct and opposing effects on activated CD44(high) CD62L(low) CD8(+) T cells in skin graft recipients. Specifically, CD154 blockade delayed alloreactive CD8(+) T cell responses, while DST accelerated them. DST inhibited the differentiation of alloreactive CD8(+) T cells into multi-cytokine producing effectors, while CD40/CD154 blockade led to the diminution of the KLRG-1(low) long-lived memory precursor population compared with either untreated or DST treated animals. Moreover, only CD154 blockade effectively inhibited CXCL1 expression and neutrophil recruitment into the graft. When combined, anti-CD154 and DST acted synergistically to profoundly diminish the absolute number of IFN-γ producing alloreactive CD8(+) T cells, and intra-graft expression of inflammatory chemokines. These findings demonstrate that the previously described ability of anti-CD154 and DST to result in alloreactive T cell deletion involves both delayed kinetics of T cell expansion and differentiation and inhibited development of KLRG-1(low) memory precursor cells.
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Affiliation(s)
- Ivana R. Ferrer
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, Georgia, United States of America
| | - Maylene E. Wagener
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, Georgia, United States of America
| | - Mingqing Song
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, Georgia, United States of America
| | - Mandy L. Ford
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, Georgia, United States of America
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