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1
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Kowli S, Minocherhomji S, Martinez OM, Busque S, Lebrec H, Maecker HT. Characterization of immune phenotypes in peripheral blood of adult renal transplant recipients using mass cytometry (CyTOF). Immunohorizons 2025; 9:vlae013. [PMID: 39965168 PMCID: PMC11841977 DOI: 10.1093/immhor/vlae013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 10/20/2024] [Indexed: 02/20/2025] Open
Abstract
Chronic immunosuppressive therapies are crucial in organ transplantation but can increase the risk of opportunistic infections and cancer over time. We investigated immune status changes in 10 kidney transplant patients and 11 age-matched healthy adults using broad in vitro stimulation of subject-derived peripheral blood mononuclear cells followed by mass cytometry by time of flight over 6 mo. Overall, the immune cells of transplant patients exhibited increased CD8+ T cell activation and differentiation compared with healthy donors, with elevated CD8+ CD57+, MIP-1β, and interferon γ production (P < 0.05, P < 0.05, and P < 0.01, respectively). CD107a and granzyme B expression were increased in CD8+ T cells and CD56bright natural killer cells (P < 0.05 and P < 0.01, respectively), while T regulatory cells had decreased interleukin-10 production (P < 0.05). These changes indicated a proinflammatory environment influenced by induction therapy and ongoing maintenance drugs. Additionally, transplant recipients displayed signs of immune modulation, including decreased tumor necrosis factor α, interferon γ, and MIP-1β expression in γδT cells (P < 0.05 and P < 0.01), and reduced interleukin-17 and granulocyte-macrophage colony-stimulating factor expression in CD8+ T memory cell subsets (P < 0.05). The diverse functional changes underscore the importance of comprehensive immune status profiling for optimizing individual treatment strategies and developing better immunosuppressants that specifically target activated cell populations.
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Affiliation(s)
- Sangeeta Kowli
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA, United States
- Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA, United States
| | - Sheroy Minocherhomji
- Amgen Inc., Thousand Oaks, CA, United States
- Eli Lilly and Company, Indianapolis, IN 46285, United States
| | - Olivia M Martinez
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA, United States
| | - Stephan Busque
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA, United States
| | - Herve Lebrec
- Amgen Inc., Thousand Oaks, CA, United States
- Sonoma Biotherapeutics, South San Francisco, CA 94080, United States
| | - Holden T Maecker
- Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University, Stanford, CA, United States
- Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA, United States
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Grosu-Bularda A, Hodea FV, Zamfirescu D, Stoian A, Teodoreanu RN, Lascăr I, Hariga CS. Exploring Costimulatory Blockade-Based Immunologic Strategies in Transplantation: Are They a Promising Immunomodulatory Approach for Organ and Vascularized Composite Allotransplantation? J Pers Med 2024; 14:322. [PMID: 38541064 PMCID: PMC10971463 DOI: 10.3390/jpm14030322] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/12/2024] [Accepted: 03/18/2024] [Indexed: 11/12/2024] Open
Abstract
The field of transplantation, including the specialized area of vascularized composite allotransplantation (VCA), has been transformed since the first hand transplant in 1998. The major challenge in VCA comes from the need for life-long immunosuppressive therapy due to its non-vital nature and a high rate of systemic complications. Ongoing research is focused on immunosuppressive therapeutic strategies to avoid toxicity and promote donor-specific tolerance. This includes studying the balance between tolerance and effector mechanisms in immune modulation, particularly the role of costimulatory signals in T lymphocyte activation. Costimulatory signals during T cell activation can have either stimulatory or inhibitory effects. Interfering with T cell activation through costimulation blockade strategies shows potential in avoiding rejection and prolonging the survival of transplanted organs. This review paper aims to summarize current data on the immunologic role of costimulatory blockade in the field of transplantation. It focuses on strategies that can be applied in vascularized composite allotransplantation, offering insights into novel methods for enhancing the success and safety of these procedures.
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Affiliation(s)
- Andreea Grosu-Bularda
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Florin-Vlad Hodea
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | | | | | - Răzvan Nicolae Teodoreanu
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Ioan Lascăr
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Cristian Sorin Hariga
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
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Huelsboemer L, Kauke-Navarro M, Reuter S, Stoegner VA, Feldmann J, Hirsch T, Kueckelhaus M, Dermietzel A. Tolerance Induction in Vascularized Composite Allotransplantation-A Brief Review of Preclinical Models. Transpl Int 2023; 36:10955. [PMID: 36846605 PMCID: PMC9946984 DOI: 10.3389/ti.2023.10955] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 01/24/2023] [Indexed: 02/11/2023]
Abstract
Pre-clinical studies are an obligatory tool to develop and translate novel therapeutic strategies into clinical practice. Acute and chronic rejection mediated by the recipient's immune system remains an important limiting factor for the (long-term) survival of vascularized composite allografts (VCA). Furthermore, high intensity immunosuppressive (IS) protocols are needed to mitigate the immediate and long-term effects of rejection. These IS regiments can have significant side-effects such as predisposing transplant recipients to infections, organ dysfunction and malignancies. To overcome these problems, tolerance induction has been proposed as one strategy to reduce the intensity of IS protocols and to thereby mitigate long-term effects of allograft rejection. In this review article, we provide an overview about animal models and strategies that have been used to induce tolerance. The induction of donor-specific tolerance was achieved in preclinical animal models and clinical translation may help improve short and long-term outcomes in VCAs in the future.
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Affiliation(s)
- Lioba Huelsboemer
- Division of Plastic and Reconstructive Surgery, School of Medicine, Yale University, New Haven, CT, United States
- Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Martin Kauke-Navarro
- Division of Plastic and Reconstructive Surgery, School of Medicine, Yale University, New Haven, CT, United States
| | - Stefan Reuter
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital Münster, Münster, Germany
| | - Viola A. Stoegner
- Division of Plastic and Reconstructive Surgery, School of Medicine, Yale University, New Haven, CT, United States
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hanover, Germany
| | - Jan Feldmann
- Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Tobias Hirsch
- Division of Plastic Surgery, Department of Trauma, Hand and Reconstructive Surgery, Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
- Department of Plastic, Reconstructive and Aesthetic Surgery, Hand Surgery, Fachklinik Hornheide, Münster, Germany
| | - Maximilian Kueckelhaus
- Division of Plastic Surgery, Department of Trauma, Hand and Reconstructive Surgery, Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
- Department of Plastic, Reconstructive and Aesthetic Surgery, Hand Surgery, Fachklinik Hornheide, Münster, Germany
| | - Alexander Dermietzel
- Division of Plastic Surgery, Department of Trauma, Hand and Reconstructive Surgery, Institute of Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
- Department of Plastic, Reconstructive and Aesthetic Surgery, Hand Surgery, Fachklinik Hornheide, Münster, Germany
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Zhang W, Schönberg A, Bassett F, Hadrian K, Hos D, Becker M, Bock F, Cursiefen C. Different Murine High-Risk Corneal Transplant Settings Vary Significantly in Their (Lymph)angiogenic and Inflammatory Cell Signatures. Invest Ophthalmol Vis Sci 2022; 63:18. [PMID: 36534386 PMCID: PMC9769342 DOI: 10.1167/iovs.63.13.18] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Purpose Pathologic conditions in the cornea, such as transplant rejection or trauma, can lead to corneal neovascularization, creating a high-risk environment that may compromise subsequent transplantation. This study aimed to evaluate the impact of different types of corneal injury on hemangiogenesis (HA), lymphangiogenesis (LA) and immune cell pattern in the cornea. Methods We used five different corneal injury models, namely, incision injury, alkali burn, suture placement, and low-risk keratoplasty, as well as high-risk keratoplasty and naïve corneas as control. One week after incision and 2 weeks after all other different injuries, corneal HA and LA were quantified by morphometric analysis. In addition, immune cell patterns of the whole cornea and the recipient rim were analyzed by immunohistochemistry. Immune cells in the draining lymph nodes (dLNs) were quantified by flow cytometry. Results Different types of corneal injury caused significantly different HA and LA responses (both P < 0.0001). The infiltration of corneal macrophages, dendritic cells, neutrophils, major histocompatibility complex (MHC) II+ cells, CD4+ T cells, and CD8+ T cells varied significantly in different high-risk settings (all P < 0.0001). Both the expression of MHC II on macrophages (P = 0.0005) and the frequency of MHC II+ dendritic cells (P = 0.0014) in the draining lymph nodes were significantly different across the various high-risk scenarios. Conclusions Murine high-risk settings caused by different underlying pathologies vary significantly in their (lymph)angiogenic and inflammatory cell patterns. Therefore, anti(lymph)angiogenic or immunomodulatory strategies to prevent and/or treat immune responses after subsequent corneal transplantation may need to be customized according to their immune-vascular "signatures."
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Affiliation(s)
- Wei Zhang
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Alfrun Schönberg
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Fiona Bassett
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Karina Hadrian
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Deniz Hos
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Martina Becker
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Felix Bock
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
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5
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Zhang W, Schönberg A, Hamdorf M, Georgiev T, Cursiefen C, Bock F. Preincubation of donor tissue with a VEGF cytokine trap promotes subsequent high-risk corneal transplant survival. Br J Ophthalmol 2021; 106:1617-1626. [PMID: 34810177 DOI: 10.1136/bjophthalmol-2021-319745] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 09/07/2021] [Indexed: 11/03/2022]
Abstract
AIMS Pathological neovascularisation of the host bed and the transplant itself is the main risk factor for graft rejection after corneal transplantation. This study aims to prevent this process by preincubation of the corneal donor tissue ex vivo with an antivascular endothelial growth factor (VEGF) cytokine trap blocking additional postsurgical hemangiogenesis and lymphangiogenesis to promote high-risk graft survival. METHODS The donor tissue was preincubated with a VEGFR1R2 cytokine trap for 24 hours prior to murine high-risk corneal transplantation (human IgG Fc was used as the control). The distribution of VEGFR1R2 Trap in the cornea was investigated by immunohistochemistry. Corneas were excised to quantify the blood vessels (BVs) and lymphatic vessels (LVs) and draining lymph nodes (dLNs) were harvested to analyse the phenotype of dendritic cells (DCs) and T cells at week 1, 2 and 8 post-transplantation. Graft survival was compared between preincubation with VEGFR1R2 Trap and human IgG Fc in high-risk recipients. RESULTS VEGFR1R2 Trap was present in the graft for at least 2 weeks after surgery and additionally diffused into the corneal recipient. BVs, LVs and macrophages in the whole cornea were significantly decreased 1-week and 2-week post-transplantation (p<0.05). In dLNs the frequency of CD11c+DCs was significantly reduced, whereas CD200R+ regulatory DCs were significantly increased after keratoplasty (p<0.05). Furthermore, long-term high-risk graft survival was significantly improved (p<0.01). CONCLUSIONS Preincubation of corneal donor tissue with a VEGFR1R2 cytokine trap can significantly promote subsequent high-risk corneal transplant survival and thereby opens new treatment avenues for high-risk corneal transplantation.
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Affiliation(s)
- Wei Zhang
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.,Department of Ophthalmology, Hebei Eye Hospital, Xingtai, Hebei, China
| | - Alfrun Schönberg
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Matthias Hamdorf
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Tihomir Georgiev
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Claus Cursiefen
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Felix Bock
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany .,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
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6
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A systematic review of immunomodulatory strategies used in skin-containing preclinical vascularized composite allotransplant models. J Plast Reconstr Aesthet Surg 2021; 75:586-604. [PMID: 34895853 DOI: 10.1016/j.bjps.2021.11.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 06/13/2021] [Accepted: 11/03/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND Acute rejection remains a vexing problem in vascularized composite allotransplantation (VCA). Available immunosuppressive regimens are successful at minimizing alloimmune response and allowing VCA in humans. However, repeated rejection episodes are common, and systemic side effects of the current standard regimen (Tacrolimus, MMF, Prednisone) are dose limiting. Novel immunomodulatory approaches to improve allograft acceptance and minimize systemic toxicity are continuously explored in preclinical models. We aimed to systematically summarize past and current approaches to help guide future research in this complex field. METHODS We conducted a systematic review of manuscripts listed in the MEDLINE and PubMed databases. For inclusion, articles had to primarily investigate the effect of a therapeutic approach on prolonging the survival of a skin-containing preclinical VCA model. Non-VCA studies, human trials, anatomical and feasibility studies, and articles written in a language other than English were excluded. We followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULTS The search retrieved 980 articles of which 112 articles were ultimately included. The majority of investigations used a rat model. An orthotopic hind limb VCA model was used in 53% of the studies. Cell and drug-based approaches were investigated 58 and 52 times, respectively. We provide a comprehensive review of immunomodulatory strategies used in VCA preclinical research over a timeframe of 44 years. CONCLUSION We identify a transition from anatomically non-specific to anatomical models mimicking clinical needs. As limb transplants have been most frequently performed, preclinical research focused on using the hind limb model. We also identify a transition from drug-based suppression therapies to cell-based immunomodulation strategies.
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7
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Bikhet M, Iwase H, Yamamoto T, Jagdale A, Foote JB, Ezzelarab M, Anderson DJ, Locke JE, Eckhoff DE, Hara H, Cooper DKC. What Therapeutic Regimen Will Be Optimal for Initial Clinical Trials of Pig Organ Transplantation? Transplantation 2021; 105:1143-1155. [PMID: 33534529 DOI: 10.1097/tp.0000000000003622] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We discuss what therapeutic regimen might be acceptable/successful in the first clinical trial of genetically engineered pig kidney or heart transplantation. As regimens based on a calcineurin inhibitor or CTLA4-Ig have proved unsuccessful, the regimen we administer to baboons is based on induction therapy with antithymocyte globulin, an anti-CD20 mAb (Rituximab), and cobra venom factor, with maintenance therapy based on blockade of the CD40/CD154 costimulation pathway (with an anti-CD40 mAb), with rapamycin, and a corticosteroid. An anti-inflammatory agent (etanercept) is administered for the first 2 wk, and adjuvant therapy includes prophylaxis against thrombotic complications, anemia, cytomegalovirus, and pneumocystis. Using this regimen, although antibody-mediated rejection certainly can occur, we have documented no definite evidence of an adaptive immune response to the pig xenograft. This regimen could also form the basis for the first clinical trial, except that cobra venom factor will be replaced by a clinically approved agent, for example, a C1-esterase inhibitor. However, none of the agents that block the CD40/CD154 pathway are yet approved for clinical use, and so this hurdle remains to be overcome. The role of anti-inflammatory agents remains unproven. The major difference between this suggested regimen and those used in allotransplantation is the replacement of a calcineurin inhibitor with a costimulation blockade agent, but this does not appear to increase the complications of the regimen.
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Affiliation(s)
- Mohamed Bikhet
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hayato Iwase
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Takayuki Yamamoto
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Abhijit Jagdale
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jeremy B Foote
- Department of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL
| | - Mohamed Ezzelarab
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Douglas J Anderson
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jayme E Locke
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Devin E Eckhoff
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
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8
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Russell AL, Prince C, Lundgren TS, Knight KA, Denning G, Alexander JS, Zoine JT, Spencer HT, Chandrakasan S, Doering CB. Non-genotoxic conditioning facilitates hematopoietic stem cell gene therapy for hemophilia A using bioengineered factor VIII. Mol Ther Methods Clin Dev 2021; 21:710-727. [PMID: 34141826 PMCID: PMC8181577 DOI: 10.1016/j.omtm.2021.04.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/29/2021] [Indexed: 01/09/2023]
Abstract
Hematopoietic stem and progenitor cell (HSPC) lentiviral gene therapy is a promising strategy toward a lifelong cure for hemophilia A (HA). The primary risks associated with this approach center on the requirement for pre-transplantation conditioning necessary to make space for, and provide immune suppression against, stem cells and blood coagulation factor VIII, respectively. Traditional conditioning agents utilize genotoxic mechanisms of action, such as DNA alkylation, that increase risk of sterility, infection, and developing secondary malignancies. In the current study, we describe a non-genotoxic conditioning protocol using an immunotoxin targeting CD117 (c-kit) to achieve endogenous hematopoietic stem cell depletion and a cocktail of monoclonal antibodies to provide transient immune suppression against the transgene product in a murine HA gene therapy model. This strategy provides high-level engraftment of hematopoietic stem cells genetically modified ex vivo using recombinant lentiviral vector (LV) encoding a bioengineered high-expression factor VIII variant, termed ET3. Factor VIII procoagulant activity levels were durably elevated into the normal range and phenotypic correction achieved. Furthermore, no immunological rejection or development of anti-ET3 immunity was observed. These preclinical data support clinical translation of non-genotoxic antibody-based conditioning in HSPC LV gene therapy for HA.
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Affiliation(s)
- Athena L. Russell
- Graduate Program in Genetics and Molecular Biology, Laney Graduate School, Emory University, Atlanta, GA 30322, USA
| | - Chengyu Prince
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Taran S. Lundgren
- Graduate Program in Molecular and Systems Pharmacology, Laney Graduate School, Emory University, Atlanta, GA 30322, USA
| | - Kristopher A. Knight
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Graduate Program in Molecular and Systems Pharmacology, Laney Graduate School, Emory University, Atlanta, GA 30322, USA
| | | | - Jordan S. Alexander
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Jaquelyn T. Zoine
- Graduate Program in Cancer Biology, Laney Graduate School, Emory University, Atlanta, GA 30322, USA
| | - H. Trent Spencer
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Expression Therapeutics, LLC, Tucker, GA 30084, USA
| | - Shanmuganathan Chandrakasan
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Christopher B. Doering
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Expression Therapeutics, LLC, Tucker, GA 30084, USA
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9
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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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10
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Peyster EG, Wang C, Ishola F, Remeniuk B, Hoyt C, Feldman MD, Margulies KB. In Situ Immune Profiling of Heart Transplant Biopsies Improves Diagnostic Accuracy and Rejection Risk Stratification. JACC Basic Transl Sci 2020; 5:328-340. [PMID: 32368693 PMCID: PMC7188920 DOI: 10.1016/j.jacbts.2020.01.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/24/2020] [Accepted: 01/24/2020] [Indexed: 12/15/2022]
Abstract
Recognizing that guideline-directed histologic grading of endomyocardial biopsy tissue samples for rejection surveillance has limited diagnostic accuracy, quantitative, in situ characterization was performed of several important immune cell types in a retrospective cohort of clinical endomyocardial tissue samples. Differences between cases were identified and were grouped by histologic grade versus clinical rejection trajectory, with significantly increased programmed death ligand 1+, forkhead box P3+, and cluster of differentiation 68+ cells suppressed in clinically evident rejections, especially cases with marked clinical-histologic discordance. Programmed death ligand 1+, forkhead box P3+, and cluster of differentiation 68+ cell proportions are also significantly higher in "never-rejection" when compared with "future-rejection." These findings suggest that in situ immune modulators regulate the severity of cardiac allograft rejection.
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Affiliation(s)
- Eliot G Peyster
- Cardiovascular Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | | | | | | | - Michael D Feldman
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kenneth B Margulies
- Cardiovascular Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania
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11
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Shahzad KA, Naeem M, Zhang L, Wan X, Song S, Pei W, Zhao C, Jin X, Shen C. Design and Optimization of PLGA Particles to Deliver Immunomodulatory Drugs for the Prevention of Skin Allograft Rejection. Immunol Invest 2019; 49:840-857. [PMID: 31809611 DOI: 10.1080/08820139.2019.1695134] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Background: Recent advancements in therapeutic strategies have attracted considerable attention to control the acute organs and tissues rejection, which is the main cause of mortality in transplant recipients. The long-term usage of immunosuppressive drugs compromises the body immunity against simple infections and decrease the patients' quality of life. Tolerance of allograft in recipients without harming the rest of host immune system is the basic idea to develop the therapeutic approaches after induction of donor-specific transplant. Methods: Controlled and targeted delivery system by using biomimetic micro and nanoparticles as carriers is an effective strategy to deplete the immune cells in response to allograft in an antigen-specific manner. Polylactic-co-glycolic acid (PLGA) is a biocompatible and biodegradable polymer, which has frequently being used as drug delivery vehicle. Results: This review focuses on the biomedical applications of PLGA based biomimetic micro and nano-sized particles in drug delivery systems to prolong the survival of alloskin graft. Conclusion: We will discuss the mediating factors for rejection of alloskin graft, selective depletion of immune cells, controlled release mechanism, physiochemical properties, size-based body distribution of PLGA particles and their effect on overall host immune system.
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Affiliation(s)
- Khawar Ali Shahzad
- Department of Microbiology and Immunology, Medical School, Southeast University , Nanjing, Jiangsu, China.,School of Pharmacy, Taizhou Polytechnic College , Taizhou, Jiangsu, China
| | - Muhammad Naeem
- Institute of Pure and Applied Biology, Zoology Division, Bahauddin Zakariya University , Multan, Pakistan
| | - Lei Zhang
- Department of Microbiology and Immunology, Medical School, Southeast University , Nanjing, Jiangsu, China.,Department of Clinical Laboratory, Lishui District People's Hospital of Nanjing , Nanjing, Jiangsu, China
| | - Xin Wan
- Department of Microbiology and Immunology, Medical School, Southeast University , Nanjing, Jiangsu, China
| | - Shilong Song
- Department of Microbiology and Immunology, Medical School, Southeast University , Nanjing, Jiangsu, China
| | - Weiya Pei
- Department of Microbiology and Immunology, Medical School, Southeast University , Nanjing, Jiangsu, China
| | - Chen Zhao
- Department of Microbiology and Immunology, Medical School, Southeast University , Nanjing, Jiangsu, China
| | - Xiaoxiao Jin
- Department of Microbiology and Immunology, Medical School, Southeast University , Nanjing, Jiangsu, China
| | - Chuanlai Shen
- Department of Microbiology and Immunology, Medical School, Southeast University , Nanjing, Jiangsu, China
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12
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Skarlis C, Marketos N, Mavragani CP. Biologics in Sjögren's syndrome. Pharmacol Res 2019; 147:104389. [DOI: 10.1016/j.phrs.2019.104389] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Revised: 08/01/2019] [Accepted: 08/05/2019] [Indexed: 12/20/2022]
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13
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Targeting the CD40-CD154 Signaling Pathway for Treatment of Autoimmune Arthritis. Cells 2019; 8:cells8080927. [PMID: 31426619 PMCID: PMC6721639 DOI: 10.3390/cells8080927] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/15/2019] [Accepted: 08/17/2019] [Indexed: 12/14/2022] Open
Abstract
Full activation of T lymphocytes requires signals from both T cell receptors and costimulatory molecules. In addition to CD28, several T cell molecules could deliver costimulatory signals, including CD154, which primarily interacts with CD40 on B-cells. CD40 is a critical molecule regulating several B-cell functions, such as antibody production, germinal center formation and cellular proliferation. Upregulated expression of CD40 and CD154 occurs in immune effector cells and non-immune cells in different autoimmune diseases. In addition, therapeutic benefits have been observed by blocking the CD40-CD154 interaction in animals with collagen-induced arthritis. Given the therapeutic success of the biologics abatacept, which blocks CD28 costimulation, and rituximab, which deletes B cells in the treatment of autoimmune arthritis, the inhibition of the CD40-CD154 axis has two advantages, namely, attenuating CD154-mediated T cell costimulation and suppressing CD40-mediated B-cell stimulation. Furthermore, blockade of the CD40-CD154 interaction drives the conversion of CD4+ T cells to regulatory T cells that mediate immunosuppression. Currently, several biological products targeting the CD40-CD154 axis have been developed and are undergoing early phase clinical trials with encouraging success in several autoimmune disorders, including autoimmune arthritis. This review addresses the roles of the CD40-CD154 axis in the pathogenesis of autoimmune arthritis and its potential as a therapeutic target.
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14
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Kadono K, Dery KJ, Hirao H, Ito T, Kageyama S, Nakamura K, Oncel D, Aziz A, Kaldas FM, Busuttil RW, Kupiec-Weglinski JW. Heme Oxygenase-1 dictates innate - adaptive immune phenotype in human liver transplantation. Arch Biochem Biophys 2019; 671:162-166. [PMID: 31299184 DOI: 10.1016/j.abb.2019.07.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 07/03/2019] [Accepted: 07/08/2019] [Indexed: 12/19/2022]
Abstract
Liver transplantation (LT) has become the standard of care for patients with end-stage liver disease and those with hepatic malignancies, while adaptive immune-dominated graft rejection remains a major challenge. Despite potent anti-inflammatory and cytoprotective functions of heme oxygenase-1 (HO-1) overexpression upon innate immune-driven hepatic ischemia reperfusion injury, its role in adaptive immune cell-driven responses remains to be elucidated. We analyzed human biopsies from LT recipients (n = 55) to determine putative association between HO-1 levels and adaptive/co-stimulatory gene expression programs in LT. HO-1 expression negatively correlated with innate (CD68, Cathepsin G, TLR4, CXCL10), adaptive (CD4, CD8, IL17) and co-stimulatory (CD28, CD80, CD86) molecules at the graft site. LT recipients with high HO-1 expression showed a trend towards improved overall survival. By demonstrating the association between graft HO-1 levels and adaptive/co-stimulatory gene programs, our study provides important insights to the role of HO-1 signaling in LT patients.
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Affiliation(s)
- Kentaro Kadono
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Kenneth J Dery
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Hirofumi Hirao
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Takahiro Ito
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Shoichi Kageyama
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Kojiro Nakamura
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Damla Oncel
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Antony Aziz
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Fady M Kaldas
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Ronald W Busuttil
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Jerzy W Kupiec-Weglinski
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
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15
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Yu X, Zheng Y, Mao R, Su Z, Zhang J. BTLA/HVEM Signaling: Milestones in Research and Role in Chronic Hepatitis B Virus Infection. Front Immunol 2019; 10:617. [PMID: 30984188 PMCID: PMC6449624 DOI: 10.3389/fimmu.2019.00617] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 03/08/2019] [Indexed: 12/27/2022] Open
Abstract
B- and T-lymphocyte attenuator (BTLA) is an immune-regulatory receptor, similar to CTLA-4 and PD-1, and is mainly expressed on B-, T-, and all mature lymphocyte cells. Herpes virus entry mediator (HVEM)-BTLA plays a critical role in immune tolerance and immune responses which are areas of intense research. However, the mechanisms of the BTLA and the BTLA/HVEM signaling pathway in human diseases remain unclear. This review describes the research milestones of BTLA and HVEM in chronological order and their role in chronic HBV infection.
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Affiliation(s)
- Xueping Yu
- Department of Infectious Diseases, First Hospital of Quanzhou, Fujian Medical University, Quanzhou, China.,Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yijuan Zheng
- Department of Infectious Diseases, First Hospital of Quanzhou, Fujian Medical University, Quanzhou, China
| | - Richeng Mao
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhijun Su
- Department of Infectious Diseases, First Hospital of Quanzhou, Fujian Medical University, Quanzhou, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
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16
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Boleto G, Allanore Y, Avouac J. Targeting Costimulatory Pathways in Systemic Sclerosis. Front Immunol 2018; 9:2998. [PMID: 30619351 PMCID: PMC6305435 DOI: 10.3389/fimmu.2018.02998] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 12/04/2018] [Indexed: 01/04/2023] Open
Abstract
Systemic sclerosis (SSc) is an autoimmune T-cell disease that is characterized by pathological fibrosis of the skin and internal organs. SSc is considered a prototype condition for studying the links between autoimmunity and fibrosis. Costimulatory pathways such as CD28/CTLA-4, ICOS-B7RP1, CD70-CD27, CD40-CD154, or OX40-OX40L play an essential role in the modulation of T-cell and inflammatory immune responses. A growing body of evidence suggests that T-cell costimulation signals might be implicated in the pathogenesis of SSc. CD28, CTLA-4, ICOS, and OX40L are overexpressed in patients with SSc, particularly in patients with cutaneous diffuse forms. In pre-clinical models of SSc, T-cell costimulation blockade with abatacept (CTLA-4-Ig) prevented and induced the regression of inflammation-driven dermal fibrosis, improved digestive involvement, prevented lung fibrosis, and attenuated pulmonary hypertension in complementary models of SSc. Likewise, potent anti-fibrotic effects were seen with the blockade of OX40L by reducing the infiltration of inflammatory cells into lesional tissues leading to decreased fibroblast activation. Concerning clinical effects, a preliminary observational study suggested some effectiveness of abatacept on inflammatory joint involvement, whereas clinical improvement of skin fibrosis was observed in a small placebo-controlled randomized trial. Currently there is one ongoing phase II clinical trial assessing the efficacy of abatacept in SSc (ASSET trial, NCT02161406). Overall, given the lack of available effective agents and the known toxic effects of immunosuppressive agents approved for use in SSc, costimulatory pathways offer the advantage of a targeted approach to costimulatory signals and potentially a better safety profile.
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Affiliation(s)
- Gonçalo Boleto
- Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016, Institut Cochin, CNRS UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Service de Rhumatologie A, Hôpital Cochin, Paris, France
| | - Yannick Allanore
- Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016, Institut Cochin, CNRS UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Service de Rhumatologie A, Hôpital Cochin, Paris, France
| | - Jérôme Avouac
- Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016, Institut Cochin, CNRS UMR8104, Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, Service de Rhumatologie A, Hôpital Cochin, Paris, France
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17
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Kubo K, Kawato Y, Nakamura K, Nakajima Y, Nakagawa TY, Hanaoka K, Oshima S, Fukahori H, Inami M, Morokata T, Higashi Y. Effective suppression of donor specific antibody production by Cathepsin S inhibitors in a mouse transplantation model. Eur J Pharmacol 2018; 838:145-152. [DOI: 10.1016/j.ejphar.2018.09.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 08/16/2018] [Accepted: 09/05/2018] [Indexed: 02/03/2023]
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18
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Grywalska E, Pasiarski M, Góźdź S, Roliński J. Immune-checkpoint inhibitors for combating T-cell dysfunction in cancer. Onco Targets Ther 2018; 11:6505-6524. [PMID: 30323625 PMCID: PMC6177399 DOI: 10.2147/ott.s150817] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Under normal conditions, the immune system responds effectively to both external and internal threats without damaging healthy tissues. Cells undergoing a neoplastic transformation are one such threat. An efficient activation of T cells is enabled by T-cell receptor (TCR) interactions with antigen-presenting class I and class II molecules of the major histocompatibility complex (MHC), co-stimulatory molecules, and cytokines. After threatening stimuli are removed from the body, the host's immune response ceases, which prevents tissue damage or chronic inflammation. The recognition of foreign antigens is highly selective, which requires multistep regulation to avoid reactions against the antigens of healthy cells. This multistep regulation includes central and peripheral tolerance toward the body's own antigens. Here, we discuss T-cell dysfunction, which leads to poor effector function against foreign antigens, including cancer. We describe selected cellular receptors implicated in T-cell dysfunction and discuss how immune-checkpoint inhibitors can help overcome T-cell dysfunction in cancer treatment.
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Affiliation(s)
- Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Lublin, Poland,
| | - Marcin Pasiarski
- Department of Hematology, Holy Cross Oncology Center of Kielce, Kielce, Poland.,Faculty of Health Sciences, Jan Kochanowski University, Kielce, Poland
| | - Stanisław Góźdź
- Faculty of Health Sciences, Jan Kochanowski University, Kielce, Poland.,Department of Oncology, Holy Cross Oncology Center of Kielce, Kielce, Poland
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Lublin, Poland,
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19
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Morris AB, Adams LE, Ford ML. Influence of T Cell Coinhibitory Molecules on CD8 + Recall Responses. Front Immunol 2018; 9:1810. [PMID: 30135685 PMCID: PMC6092517 DOI: 10.3389/fimmu.2018.01810] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 07/23/2018] [Indexed: 12/15/2022] Open
Abstract
T cell co-signaling molecules play an important role in fine-tuning the strength of T cell activation during many types of immune responses, including infection, cancer, transplant rejection, and autoimmunity. Over the last few decades, intense research into these cosignaling molecules has provided rich evidence to suggest that cosignaling molecules may be harnessed for the treatment of immune-related diseases. In particular, coinhibitory molecules such as programmed-death 1, 2B4, BTLA, TIGIT, LAG-3, TIM-3, and CTLA-4 inhibit T cell responses by counteracting TCR and costimulatory signals, leading to the inhibition of proliferation and effector function and the downregulation of activation and adhesion molecules at the cell surface. While many reviews have focused on the role of coinhibitory molecules in modifying primary CD8+ T cell responses, in this review, we will consider the complex role of coinhibitory molecules in altering CD8+ T cell recall potential. As memory CD8+ T cell responses are critical for protective memory responses in infection and cancer and contribute to potentially pathogenic memory responses in transplant rejection and autoimmunity, understanding the role of coinhibitory receptor control of memory T cells may illuminate important aspects of therapeutically targeting these pathways.
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Affiliation(s)
- Anna B Morris
- Department of Surgery, Emory University, Atlanta, GA, United States
| | - Layne E Adams
- Department of Surgery, Emory University, Atlanta, GA, United States
| | - Mandy L Ford
- Department of Surgery, Emory University, Atlanta, GA, United States
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20
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CTLA4Ig Improves Murine iTreg Induction via TGF β and Suppressor Function In Vitro. J Immunol Res 2018; 2018:2484825. [PMID: 30057914 PMCID: PMC6051081 DOI: 10.1155/2018/2484825] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 04/26/2018] [Accepted: 05/29/2018] [Indexed: 12/30/2022] Open
Abstract
Blockade of the CD28:CD80/86 costimulatory pathway has been shown to be potent in blocking T cell activation in vitro and in vivo. The costimulation blocker CTLA4Ig has been approved for the treatment of autoimmune diseases and transplant rejection. The therapeutic application of regulatory T cells (Tregs) has recently gained much attention for its potential of improving allograft survival. However, neither costimulation blockade with CTLA4Ig nor Treg therapy induces robust tolerance on its own. Combining CTLA4Ig with Treg therapy would be an attractive approach for minimizing immunosuppression or for possibly achieving tolerance. However, since the CD28 pathway is more complex than initially thought, the question arose whether blocking CD80/86 would inadvertently impact immunological tolerance by interfering with Treg generation and function. We therefore wanted to investigate the compatibility of CTLA4Ig with regulatory T cells by evaluating direct effects of CTLA4Ig on murine Treg generation and function in vitro. For generation of polyclonal-induced Tregs, we utilized an APC-free in vitro system and added titrated doses of CTLA4Ig at different time points. Phenotypical characterization by flow cytometry and functional characterization in suppressor assays did not reveal negative effects by CTLA4Ig. The costimulation blocker CTLA4Ig does not impair but rather improves murine iTreg generation and suppressor function in vitro.
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21
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The Costimulatory Pathways and T Regulatory Cells in Ischemia-Reperfusion Injury: A Strong Arm in the Inflammatory Response? Int J Mol Sci 2018; 19:ijms19051283. [PMID: 29693595 PMCID: PMC5983665 DOI: 10.3390/ijms19051283] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 04/14/2018] [Accepted: 04/19/2018] [Indexed: 02/08/2023] Open
Abstract
Costimulatory molecules have been identified as crucial regulators in the inflammatory response in various immunologic disease models. These molecules are classified into four different families depending on their structure. Here, we will focus on various ischemia studies that use costimulatory molecules as a target to reduce the inherent inflammatory status. Furthermore, we will discuss the relevant role of T regulatory cells in these inflammatory mechanisms and the costimulatory pathways in which they are involved.
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22
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Bigenzahn S, Juergens B, Mahr B, Pratschke J, Koenigsrainer A, Becker T, Fuchs D, Brandacher G, Kainz A, Muehlbacher F, Wekerle T. No augmentation of indoleamine 2,3-dioxygenase (IDO) activity through belatacept treatment in liver transplant recipients. Clin Exp Immunol 2018; 192:233-241. [PMID: 29271486 DOI: 10.1111/cei.13093] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 10/30/2017] [Accepted: 11/20/2017] [Indexed: 01/18/2023] Open
Abstract
Belatacept is a second-generation cytotoxic T lymphocyte antigen (CTLA)-4 immunoglobulin (Ig) fusion protein approved for immunosuppression in renal transplant recipients. It was designed intentionally to interrupt co-stimulation via CD28 by binding to its ligands B7·1 and B7·2. Experimental evidence suggests a potential additional mechanism for CTLA-4 Ig compounds through binding to B7 molecules expressed on antigen-presenting cells (APCs) and up-regulation of indoleamine 2,3-dioxygenase (IDO), an immunomodulating enzyme that catalyzes the degradation of tryptophan to kynurenine and that down-regulates T cell immunity. So far it remains unknown whether belatacept up-regulates IDO in transplant recipients. We therefore investigated whether belatacept therapy enhances IDO activity in liver transplant recipients enrolled in a multi-centre, investigator-initiated substudy of the Phase II trial of belatacept in liver transplantation (IM103-045). Tryptophan and kynurenine serum levels were measured during the first 6 weeks post-transplant in liver transplant patients randomized to receive either belatacept or tacrolimus-based immunosuppression. There was no significant difference in IDO activity, as indicated by the kynurenine/tryptophan ratio, between belatacept and tacrolimus-treated patients in per-protocol and in intent-to-treat analyses. Moreover, no evidence was found that belatacept affects IDO in human dendritic cells (DC) in vitro. These data provide evidence that belatacept is not associated with detectable IDO induction in the clinical transplant setting compared to tacrolimus-treated patients.
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Affiliation(s)
- S Bigenzahn
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
| | - B Juergens
- Division of Transplantation Immunology, Children's Cancer Research Institute, St Anna Children's Hospital, Vienna, Austria
| | - B Mahr
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
| | - J Pratschke
- Department of General, Visceral, and Transplantation Surgery, Charité, Berlin, Germany
| | - A Koenigsrainer
- Department of General, Visceral and Transplant Surgery, University Hospital Tuebingen, Tuebingen, Germany
| | - T Becker
- Department of General, Visceral and Transplant Surgery, Hanover Medical School, Hanover, Germany
| | - D Fuchs
- Division of Biological Chemistry, Biocentre, Innsbruck Medical University, Innsbruck, Austria
| | - G Brandacher
- Department of General and Transplant Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - A Kainz
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - F Muehlbacher
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
| | - T Wekerle
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
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23
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Evolving Approaches in the Identification of Allograft-Reactive T and B Cells in Mice and Humans. Transplantation 2017; 101:2671-2681. [PMID: 28604446 DOI: 10.1097/tp.0000000000001847] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Whether a transplanted allograft is stably accepted, rejected, or achieves immunological tolerance is dependent on the frequency and function of alloreactive lymphocytes, making the identification and analysis of alloreactive T and B cells in transplant recipients critical for understanding mechanisms, and the prediction of allograft outcome. In animal models, tracking the fate of graft-reactive T and B cells allows investigators to uncover their biology and develop new therapeutic strategies to protect the graft. In the clinic, identification and quantification of graft-reactive T and B cells allows for the early diagnosis of immune reactivity and therapeutic intervention to prevent graft loss. In addition to rejection, probing of T and B cell fate in vivo provides insights into the underlying mechanisms of alloimmunity or tolerance that may lead to biomarkers predicting graft fate. In this review, we discuss existing and developing approaches to track and analyze alloreactive T and B cells in mice and humans and provide examples of discoveries made utilizing these techniques. These approaches include mixed lymphocyte reactions, trans-vivo delayed-type hypersensitivity, enzyme-linked immunospot assays, the use of antigen receptor transgenic lymphocytes, and utilization of peptide-major histocompatibility multimers, along with imaging techniques for static multiparameter analysis or dynamic in vivo tracking. Such approaches have already refined our understanding of the alloimmune response and are pointing to new ways to improve allograft outcomes in the clinic.
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24
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Associations between HVEM/LIGHT/BTLA/CD160 polymorphisms and the occurrence of antibody-mediate rejection in renal transplant recipients. Oncotarget 2017; 8:100079-100094. [PMID: 29245962 PMCID: PMC5725004 DOI: 10.18632/oncotarget.21941] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 08/19/2017] [Indexed: 12/25/2022] Open
Abstract
Antibody-mediated rejection (ABMR) is a serious complications that can occur following renal transplantation. The production of donor-specific antibodies by the humoral immune response can trigger costimulatory signals, which are crucial in activating immune cells, and therefore, playing a potential role in ABMR. To investigate the role of HVEM/LIGHT/BTLA/CD160 polymorphisms in ABMR, we retrospectively analyzed 200 renal transplant recipients. We adopted next-generation sequencing (NGS) to identify HVEM/LIGHT/BTLA/CD160 single-nucleotide polymorphisms (SNPs) in the genotypes of these patients. We divided the patients into two groups: those with ABMR and those who were stable. We adopted multiple models and performed regression analysis after adjusting for multiple confounding variables, to determine the correlation between the SNPs and ABMR. We obtained 41 high-quality SNPs readouts. However, we did not observe any significant association between these polymorphisms and the pathogenesis of ABMR in any of the models.Nevertheless, since there is evidence suggesting the involvement of costimulatory signals in graft rejection, further research should be conducted to better understand how genetic polymorphisms may be involved in ABMR.
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25
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Oh AL, Mahmud D, Nicolini B, Mahmud N, Senyuk V, Patel PR, Bonetti E, Arpinati M, Ferrara JLM, Rondelli D. T Cell-Mediated Rejection of Human CD34 + Cells Is Prevented by Costimulatory Blockade in a Xenograft Model. Biol Blood Marrow Transplant 2017; 23:2048-2056. [PMID: 28818684 DOI: 10.1016/j.bbmt.2017.08.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 08/07/2017] [Indexed: 11/28/2022]
Abstract
A xenograft model of stem cell rejection was developed by co-transplantating human CD34+ and allogeneic CD3+ T cells into NOD-scid ɣ-chainnull mice. T cells caused graft failure when transplanted at any CD34/CD3 ratio between 1:50 and 1:.1. Kinetics experiments showed that 2 weeks after transplantation CD34+ cells engrafted the marrow and T cells expanded in the spleen. Then, at 4 weeks only memory T cells populated both sites and rejected CD34+ cells. Blockade of T cell costimulation was tested by injecting the mice with abatacept (CTLA4-IgG1) from day -1 to +27 (group A), from day -1 to +13 (group B), or from day +14 to +28 (group C). On day +56 groups B and C had rejected the graft, whereas in group A graft failure was completely prevented, although with lower stem cell engraftment than in controls (P = .03). Retransplantation of group A mice with same CD34+ cells obtained a complete reconstitution of human myeloid and B cell lineages and excluded latent alloreactivity. In this first xenograft model of stem cell rejection we showed that transplantation of HLA mismatched CD34+ cells may be facilitated by treatment with abatacept and late stem cell boost.
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Affiliation(s)
- Annie L Oh
- Division of Hematology/Oncology, University of Illinois Hospital & Health Sciences System, Chicago, Illinois
| | - Dolores Mahmud
- Division of Hematology/Oncology, University of Illinois Hospital & Health Sciences System, Chicago, Illinois
| | - Benedetta Nicolini
- Division of Hematology/Oncology, University of Illinois Hospital & Health Sciences System, Chicago, Illinois; Department of Hematology/Oncology "Seragnoli", University of Bologna, Bologna, Italy
| | - Nadim Mahmud
- Division of Hematology/Oncology, University of Illinois Hospital & Health Sciences System, Chicago, Illinois; University of Illinois Cancer Center, Chicago, Illinois
| | - Vitalyi Senyuk
- Division of Hematology/Oncology, University of Illinois Hospital & Health Sciences System, Chicago, Illinois
| | - Pritesh R Patel
- Division of Hematology/Oncology, University of Illinois Hospital & Health Sciences System, Chicago, Illinois; University of Illinois Cancer Center, Chicago, Illinois
| | - Elisa Bonetti
- Division of Hematology/Oncology, University of Illinois Hospital & Health Sciences System, Chicago, Illinois
| | - Mario Arpinati
- Department of Hematology/Oncology "Seragnoli", University of Bologna, Bologna, Italy
| | - James L M Ferrara
- Pediatric Hematology-Oncology, Mount Sinai School of Medicine, New York, New York
| | - Damiano Rondelli
- Division of Hematology/Oncology, University of Illinois Hospital & Health Sciences System, Chicago, Illinois; University of Illinois Cancer Center, Chicago, Illinois; University of Illinois Center for Global Health, Chicago, Illinois.
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T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia. Transpl Immunol 2017; 43-44:54-59. [DOI: 10.1016/j.trim.2017.07.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 07/25/2017] [Accepted: 07/26/2017] [Indexed: 01/24/2023]
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Schütte-Nütgen K, Boenisch O, Harrach H, Casey A, Guleria I, Najafian N, Sayegh MH, Gerard CJ, Subramaniam M. Divergent Function of Programmed Death-Ligand 1 in Donor Tissue versus Recipient Immune System in a Murine Model of Bronchiolitis Obliterans. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1368-1379. [PMID: 28427861 PMCID: PMC5455059 DOI: 10.1016/j.ajpath.2017.02.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 02/06/2017] [Indexed: 11/17/2022]
Abstract
Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue. Although PD-L1 deficiency in donor tissue worsened histopathological outcome, and increased systemic inflammatory response, recipient PD-L1 deficiency induced opposite effects. Mechanistic studies revealed PD-L1-deficient recipients were hyporesponsive toward alloantigen, despite increased numbers of CD8+ effector T cells. The function of PD-L1 on T cells after unspecific stimulation was dependent on both cell type and strength of stimulation. This novel function of recipient PD-L1 may result from the high degree of T-cell activation within the highly immunogenic milieu of the transplanted tissue. In this model, both decreased T-cell alloimmune responses and the reduction of BO in PD-L1-deficient recipients suggest a potential therapeutic role of selectively blocking PD-L1 in the recipient. Further investigation is warranted to determine the impact of this finding embedded in the complex pathophysiological context of BO.
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Affiliation(s)
- Katharina Schütte-Nütgen
- Pulmonary Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Internal Medicine D, University Hospital Münster, Münster, Germany
| | - Olaf Boenisch
- Transplantation Research Center, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Hakima Harrach
- Pulmonary Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Alicia Casey
- Pulmonary Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Indira Guleria
- Transplantation Research Center, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Nader Najafian
- Transplantation Research Center, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Craig J Gerard
- Pulmonary Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Meera Subramaniam
- Pulmonary Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
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da Silva MB, da Cunha FF, Terra FF, Camara NOS. Old game, new players: Linking classical theories to new trends in transplant immunology. World J Transplant 2017; 7:1-25. [PMID: 28280691 PMCID: PMC5324024 DOI: 10.5500/wjt.v7.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/16/2016] [Accepted: 12/07/2016] [Indexed: 02/05/2023] Open
Abstract
The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.
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29
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Chen QQ, Chen M, Zhang LH, Zeng Y, Qi-Cai L, Yang XL, Lin XC. Costimulation blockade by combining CTLA4Ig with anti-CD40L mAb markedly inhibits the inflammatory response of experimental autoimmune myocarditis. EUR J INFLAMM 2017. [DOI: 10.1177/1721727x16686980] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The aim of this study was to investigate the effect of costimulation blockade with cytotoxic T-lymphocyte-associated-antigen 4-immunoglobulin (CTLA4Ig) and anti-CD40L monoclonal antibody (anti-CD40L mAb) on an experimental autoimmune myocarditis (EAM) mouse model. Characteristics of myocardial tissue were observed by hematoxylin and eosin (H&E) staining. The messenger RNA (mRNA) levels of CTLA4, CD40L, IFN-γ, and IL-4 were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Serum concentrations of IFN-γ and IL-4 were determined by ELISA. After immune intervention, the inflammatory score, mRNA levels of CTLA4 and CD40L, and IFN-γ level were decreased. Furthermore, these parameters in the combinational intervention group (blockade by CTLA4Ig and anti-CD40L mAb) were significantly decreased, compared to the single intervention group (blockade by CTLA4Ig or anti-CD40L mAb). However, after costimulation, blockade serum IL-4 levels were increased. Therefore, costimulation blockade by combination CTLA4Ig and anti-CD40L mAb could more effectively inhibit the inflammatory response of EAM than single use of CTLA4Ig or anti-CD40L mAb.
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Affiliation(s)
- Qing-Quan Chen
- Department of Laboratory Medicine, Medical Technology and Engineering College, Fujian Medical University, Fuzhou, Fujian, PR China
| | - Min Chen
- Department of Laboratory Medicine, Medical Technology and Engineering College, Fujian Medical University, Fuzhou, Fujian, PR China
| | - Li-Hua Zhang
- Department of Laboratory Medicine, the Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian, PR China
| | - Yu Zeng
- Department of Laboratory Medicine, Medical Technology and Engineering College, Fujian Medical University, Fuzhou, Fujian, PR China
| | - Liu Qi-Cai
- Department of Laboratory Medicine, Medical Technology and Engineering College, Fujian Medical University, Fuzhou, Fujian, PR China
- Department of Laboratory Medicine, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, PR China
| | - Xiu-Lin Yang
- Department of Laboratory Medicine, Medical Technology and Engineering College, Fujian Medical University, Fuzhou, Fujian, PR China
| | - Xu-Chen Lin
- Department of Laboratory Medicine, Medical Technology and Engineering College, Fujian Medical University, Fuzhou, Fujian, PR China
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Bone marrow chimerism as a strategy to produce tolerance in solid organ allotransplantation. Curr Opin Organ Transplant 2016; 21:595-602. [PMID: 27805947 DOI: 10.1097/mot.0000000000000366] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
PURPOSE OF REVIEW Clinical transplant tolerance has been most successfully achieved combining hematopoietic chimerism with kidney transplantation. This review outlines this strategy in animal models and human transplantation, and possible clinical challenges. RECENT FINDINGS Kidney transplant tolerance has been achieved through chimerism in several centers beginning with Massachusetts General Hospital's success with mixed chimerism in human leukocyte antigen (HLA)-mismatched patients and the Stanford group with HLA-matched patients, and the more recent success of the Northwestern protocol achieving full chimerism. This has challenged the original view that stable mixed chimerism is necessary for organ graft tolerance. However, among the HLA-mismatched kidney transplant-tolerant patients, loss of mixed chimerism does not lead to renal-graft rejection, and the development of host Foxp3+ regulatory T cells has been observed. Recent animal models suggest that graft tolerance through bone marrow chimerism occurs through both clonal deletion and regulatory immune cells. Further, Tregs have been shown to improve chimerism in animal models. SUMMARY Animal studies continue to suggest ways to improve our current clinical strategies. Advances in chimerism protocols suggest that tolerance may be clinically achievable with relative safety for HLA-mismatched kidney transplants.
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31
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Diehl R, Ferrara F, Müller C, Dreyer AY, McLeod DD, Fricke S, Boltze J. Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches. Cell Mol Immunol 2016; 14:146-179. [PMID: 27721455 PMCID: PMC5301156 DOI: 10.1038/cmi.2016.39] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 05/30/2016] [Accepted: 05/30/2016] [Indexed: 02/06/2023] Open
Abstract
Almost every experimental treatment strategy using non-autologous cell, tissue or organ transplantation is tested in small and large animal models before clinical translation. Because these strategies require immunosuppression in most cases, immunosuppressive protocols are a key element in transplantation experiments. However, standard immunosuppressive protocols are often applied without detailed knowledge regarding their efficacy within the particular experimental setting and in the chosen model species. Optimization of such protocols is pertinent to the translation of experimental results to human patients and thus warrants further investigation. This review summarizes current knowledge regarding immunosuppressive drug classes as well as their dosages and application regimens with consideration of species-specific drug metabolization and side effects. It also summarizes contemporary knowledge of novel immunomodulatory strategies, such as the use of mesenchymal stem cells or antibodies. Thus, this review is intended to serve as a state-of-the-art compendium for researchers to refine applied experimental immunosuppression and immunomodulation strategies to enhance the predictive value of preclinical transplantation studies.
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Affiliation(s)
- Rita Diehl
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | - Fabienne Ferrara
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany.,Institute of Vegetative Physiology, Charite University Medicine and Center for Cardiovascular Research, Berlin 10115, Germany
| | - Claudia Müller
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | - Antje Y Dreyer
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | | | - Stephan Fricke
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany
| | - Johannes Boltze
- Fraunhofer-Institute for Cell Therapy and Immunology, Leipzig 04103, Germany.,Fraunhofer Research Institution for Marine Biotechnology and Institute for Medical and Marine Biotechnology, University of Lübeck, Lübeck 23562, Germany
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32
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Baranyi U, Farkas AM, Hock K, Mahr B, Linhart B, Gattringer M, Focke-Tejkl M, Petersen A, Wrba F, Rülicke T, Valenta R, Wekerle T. Cell Therapy for Prophylactic Tolerance in Immunoglobulin E-mediated Allergy. EBioMedicine 2016; 7:230-9. [PMID: 27322476 PMCID: PMC4909362 DOI: 10.1016/j.ebiom.2016.03.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 03/15/2016] [Accepted: 03/18/2016] [Indexed: 12/20/2022] Open
Abstract
Background Therapeutic strategies for the prophylaxis of IgE-mediated allergy remain an unmet medical need. Cell therapy is an emerging approach with high potential for preventing and treating immunological diseases. We aimed to develop a cell-based therapy inducing permanent allergen-specific immunological tolerance for preventing IgE-mediated allergy. Methods Wild-type mice were treated with allergen-expressing bone marrow cells under a short course of tolerogenic immunosuppression (mTOR inhibition and costimulation blockade). Bone marrow was retrieved from a novel transgenic mouse ubiquitously expressing the major grass pollen allergen Phl p 5 as a membrane-anchored protein (BALB/c-Tg[Phlp5-GFP], here mPhl p 5). After transplantation recipients were IgE-sensitized at multiple time points with Phl p 5 and control allergen. Results Mice treated with mPhl p 5 bone marrow did not develop Phl p 5-specific IgE (or other isotypes) despite repeated administration of the allergen, while mounting and maintaining a strong humoral response towards the control allergen. Notably, Phl p 5-specific T cell responses and allergic airway inflammation were also completely prevented. Interestingly allergen-specific B cell tolerance was maintained independent of Treg functions indicating deletional tolerance as underlying mechanism. Conclusion This proof-of-concept study demonstrates that allergen-specific immunological tolerance preventing occurrence of allergy can be established through a cell-based therapy employing allergen-expressing leukocytes.
Avoidance of IgE-mediated allergy is established by development of a tolerogenic cell-based protocol. Transplantation of syngeneic allergen-bearing bone marrow cells into recipients leads to tolerance towards the introduced allergen. Prevention of T-and B-cell responses and allergic asthma is induced by cell transfer with non-toxic pretreatment. IgE-mediated allergy affects about 30% of the population in industrialized countries. To prevent allergy we developed a cell-based protocol with the concept to modify body's own cells to express an allergen and to reinfuse those modified cells. This concept leads to avoidance of allergic reactions after allergen contact such as specific IgE production and the development of allergic asthma. This is demonstrated in a syngeneic model in mice (i.e. autologous in human) by transplanting bone marrow cells of a unique allergen-expressing transgenic mouse into pretreated recipients.
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Affiliation(s)
- Ulrike Baranyi
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Andreas M Farkas
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Karin Hock
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Benedikt Mahr
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Birgit Linhart
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center of Physiology and Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Martina Gattringer
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Margit Focke-Tejkl
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center of Physiology and Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Arnd Petersen
- Research Center Borstel, Clinical and Molecular Allergology, Borstel, Germany
| | - Fritz Wrba
- Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria
| | - Thomas Rülicke
- Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Rudolf Valenta
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Center of Physiology and Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Thomas Wekerle
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria.
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Kraus AK, Chen J, Edenhofer I, Ravens I, Gaspert A, Cippà PE, Mueller S, Wuthrich RP, Segerer S, Bernhardt G, Fehr T. The Role of T Cell Costimulation via DNAM-1 in Kidney Transplantation. PLoS One 2016; 11:e0147951. [PMID: 26840537 PMCID: PMC4739582 DOI: 10.1371/journal.pone.0147951] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 01/11/2016] [Indexed: 11/19/2022] Open
Abstract
DNAX accessory protein-1 (DNAM-1, CD226) is a co-stimulatory and adhesion molecule expressed mainly by natural killer cells and T cells. DNAM-1 and its two ligands CD112 and CD155 are important in graft-versus-host disease, but their role in solid organ transplantation is largely unknown. We investigated the relevance of this pathway in a mouse kidney transplantation model. CD112 and CD155 are constitutively expressed on renal tubular cells and strongly upregulated in acutely rejected renal allografts. In vitro DNAM-1 blockade during allogeneic priming reduced the allospecific T cell response but not the allospecific cytotoxicity against renal tubular epithelial cells. Accordingly, absence of DNAM-1 in recipient mice or absence of CD112 or CD155 in the kidney allograft did not significantly influence renal function and severity of rejection after transplantation, but led to a higher incidence of infarcts in CD112 and CD155 deficient kidney allografts. Thus, DNAM-1 blockade is not effective in preventing transplant rejection. Despite of being highly expressed, CD112 and CD155 do not appear to play a major immunogenic role in kidney transplantation. Considering the high incidence of renal infarcts in CD112 and CD155 deficient grafts, blocking these molecules might be detrimental.
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Affiliation(s)
- Anna K. Kraus
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Jin Chen
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Ilka Edenhofer
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Inga Ravens
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Ariana Gaspert
- Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Pietro E. Cippà
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Steffen Mueller
- Department of Molecular Genetics and Microbiology, Stony Brook University, New York, New York, United States of America
| | - Rudolf P. Wuthrich
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Stephan Segerer
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | | | - Thomas Fehr
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
- * E-mail:
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Lal G, Kulkarni N, Nakayama Y, Singh AK, Sethi A, Burrell BE, Brinkman CC, Iwami D, Zhang T, Hehlgans T, Bromberg JS. IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance. Immunol Lett 2016; 170:52-63. [PMID: 26772435 DOI: 10.1016/j.imlet.2016.01.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 12/31/2015] [Accepted: 01/02/2016] [Indexed: 12/21/2022]
Abstract
B cells are known to control CD4T cell differentiation in secondary lymphoid tissues. We hypothesized that IL-10 expression by marginal zone precursor (MZP) regulatory B cells controls the differentiation and positioning of effector and regulatory T cells during tolerization. Costimulatory blockade with donor-specific transfusion (DST) and anti-CD40L mAb in C57BL/6 mice induced tolerance to allogeneic cardiac allograft. B cell depletion or IL-10 deficiency in B cells prevented tolerance, resulting in decreased follicular regulatory CD4(+) T cells (Tfr) and increased IL-21 expression by T follicular helper (Tfh) cells in the B cell and T cell zones. IL-21 acted with IL-6 to induce CCR6(+) Th17 that caused rejection. Deficiency or blockade of IL-6, IL-21, IL-21R, or CCR6 prevented B cell depletion-induced acute cellular rejection; while agonistic mCCL20-Ig induced rejection. Adoptive transfer of IL-10(+/+) MZP in tolerogen treated CD19-Cre(+/-):IL-10(fl/fl) mice rescued the localization of Tfh and Tfr cells in the B cell follicle and prevented allograft rejection. MZP B cell IL-10 is necessary for tolerance and controls the differentiation and position of Th17, Tfh and Tfr cells in secondary lymphoid tissues. This has implications for understanding tolerance induction and how B cell depletion may prevent tolerance.
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Affiliation(s)
- Girdhari Lal
- National Centre for Cell Science, Pune, MH, India.
| | | | - Yumi Nakayama
- Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Amit K Singh
- National Centre for Cell Science, Pune, MH, India
| | | | - Bryna E Burrell
- Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - C Colin Brinkman
- Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Daiki Iwami
- Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Tianshu Zhang
- Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Thomas Hehlgans
- Institute for Immunology, University of Regensburg, Regensburg, Germany
| | - Jonathan S Bromberg
- Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
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Ruiz P, Maldonado P, Hidalgo Y, Sauma D, Rosemblatt M, Bono MR. Alloreactive Regulatory T Cells Allow the Generation of Mixed Chimerism and Transplant Tolerance. Front Immunol 2015; 6:596. [PMID: 26635810 PMCID: PMC4655502 DOI: 10.3389/fimmu.2015.00596] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Accepted: 11/06/2015] [Indexed: 01/27/2023] Open
Abstract
The induction of donor-specific transplant tolerance is one of the main goals of modern immunology. Establishment of a mixed chimerism state in the transplant recipient has proven to be a suitable strategy for the induction of long-term allograft tolerance; however, current experimental recipient preconditioning protocols have many side effects, and are not feasible for use in future therapies. In order to improve the current mixed chimerism induction protocols, we developed a non-myeloablative bone-marrow transplant (NM-BMT) protocol using retinoic acid (RA)-induced alloantigen-specific Tregs, clinically available immunosuppressive drugs, and lower doses of irradiation. We demonstrate that RA-induced alloantigen-specific Tregs in addition to a NM-BMT protocol generates stable mixed chimerism and induces tolerance to allogeneic secondary skin allografts in mice. Therefore, the establishment of mixed chimerism through the use of donor-specific Tregs rather than non-specific immunosuppression could have a potential use in organ transplantation.
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Affiliation(s)
- Paulina Ruiz
- Departmento de Biología, Facultad de Ciencias, Universidad de Chile , Santiago , Chile ; Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile , Santiago , Chile
| | - Paula Maldonado
- Departmento de Biología, Facultad de Ciencias, Universidad de Chile , Santiago , Chile
| | - Yessia Hidalgo
- Departmento de Biología, Facultad de Ciencias, Universidad de Chile , Santiago , Chile
| | - Daniela Sauma
- Departmento de Biología, Facultad de Ciencias, Universidad de Chile , Santiago , Chile
| | - Mario Rosemblatt
- Departmento de Biología, Facultad de Ciencias, Universidad de Chile , Santiago , Chile ; Fundación Ciencia y Vida , Santiago , Chile ; Facultad de Ciencias Biológicas, Universidad Andres Bello , Santiago , Chile
| | - Maria Rosa Bono
- Departmento de Biología, Facultad de Ciencias, Universidad de Chile , Santiago , Chile
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Interleukin-10 From Marginal Zone Precursor B-Cell Subset Is Required for Costimulatory Blockade-Induced Transplantation Tolerance. Transplantation 2015; 99:1817-28. [PMID: 25839706 DOI: 10.1097/tp.0000000000000718] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Blocking CD40-CD40L costimulatory signals induces transplantation tolerance. Although B-cell depletion prevents alloantibody formation, nonhumoral functions of B cells in tolerance have not been well characterized. We investigated whether specific subsets of B cell or B cell-derived interleukin (IL)-10 contribute to tolerance. METHODS Wild type C57BL/6, or B cell-specific interleukin (IL)-10 (CD19-Cre::IL-10) mice, received vascularized BALB/c cardiac allografts. BALB/c donor-specific splenocyte transfusion and anti-CD40L monoclonal antibody were used as tolerogen. B cells were depleted with antimouse CD20 monoclonal antibody. Various B-cell subsets were purified and characterized by flow cytometry, reverse transcription polymerase chain reaction, and adoptive transfer. RESULTS B-cell depletion prevented costimulatory blockade-induced allogeneic tolerance. Costimulatory blockade increased IL-10 in marginal zone precursor (MZP) B cells, but not other subsets. In particular, costimulatory blockade did not change other previously defined regulatory B-cell subsets (Breg), including CD5CD1d Breg or expression of TIM1 or TIM4 on these Breg or other Breg cell subsets. Costimulatory blockade also induced IL-21R expression in MZP B cells, and IL-21R MZP B cells expressed even more IL-10. B-cell depletion or IL-10 deficiency in B cells prevented tolerance in a cardiac allograft model, resulting in rapid acute cardiac allograft rejection. Adoptive transfer of wild type MZP B cells but not other subsets to B cell-specific IL-10 deficient mice prevented graft rejection. CONCLUSIONS CD40 costimulatory blockade induces MZP B cell IL-10 which is necessary for tolerance. These observations have implications for understanding tolerance induction and how B cell depletion may prevent tolerance.
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37
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Gattringer M, Baranyi U, Pilat N, Hock K, Klaus C, Ramsey HE, Wrba F, Valenta R, Wekerle T. Anti-OX40L alone or in combination with anti-CD40L and CTLA4Ig does not inhibit the humoral and cellular response to a major grass pollen allergen. Clin Exp Allergy 2015; 46:354-64. [PMID: 26464312 DOI: 10.1111/cea.12661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 09/22/2015] [Accepted: 09/24/2015] [Indexed: 11/30/2022]
Abstract
BACKGROUND IgE-mediated allergy is a common disease characterized by a harmful immune response towards otherwise harmless environmental antigens. Induction of specific immunological non-responsiveness towards allergens would be a desirable goal. Blockade of costimulatory pathways is a promising strategy to modulate the immune response in an antigen-specific manner. Recently, OX40 (CD134) was identified as a costimulatory receptor important in Th2-mediated immune responses. Moreover, synergy between OX40 blockade and 'conventional' costimulation blockade (anti-CD40L, CTLA4Ig) was observed in models of alloimmunity. OBJECTIVE We investigated the potential of interfering with OX40 alone or in combination with CD40/CD28 signals to influence the allergic immune response. METHODS The OX40 pathway was investigated in an established murine model of IgE-mediated allergy where BALB/c mice are repeatedly immunized with the clinically relevant grass pollen allergen Phl p 5. Groups were treated with combinations of anti-OX40L, CTLA4Ig and anti-CD40L. In selected mice, Tregs were depleted with anti-CD25. RESULTS Blockade of OX40L alone at the time of first or second immunization did not modulate the allergic response on the humoral or effector cell levels but slightly on T cell responses. Administration of a combination of anti-CD40L/CTLA4Ig delayed the allergic immune response, but antibody production could not be inhibited after repeated immunization even though the allergen-specific T cell response was suppressed in the long run. Notably, additional blockade of OX40L had no detectable supplementary effect. Immunomodulation partly involved regulatory T cells as depletion of CD25(+) cells led to restored T cell proliferation. CONCLUSIONS AND CLINICAL RELEVANCE Collectively, our data provide evidence that the allergic immune response towards Phl p 5 is independent of OX40L, although reduction on T cell responses and slightly on the asthmatic phenotype was detectable. Besides, no relevant synergistic effect of OX40L blockade in addition to CD40L/CD28 blockade could be detected. Thus, the therapeutic potential of OX40L blockade for IgE-mediated allergy appears to be ineffective in this setting.
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Affiliation(s)
- M Gattringer
- Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - U Baranyi
- Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - N Pilat
- Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - K Hock
- Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - C Klaus
- Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - H E Ramsey
- Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - F Wrba
- Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria
| | - R Valenta
- Department of Pathophysiology and Allergy Research, Division of Immunopathology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - T Wekerle
- Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
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38
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Abstract
PURPOSE OF REVIEW There are several monoclonal and polyclonal antibodies used in renal transplantation today, this article will discuss several agents, their updates and newer agents. RECENT FINDINGS Antithymocyte globulin and interleukin-2 (IL-2) receptor blocker continue to be used as induction agents. The risk of acute rejection was higher in IL-2 receptor blockers mainly in the first year, but graft survivals were similar in both groups long term. Belatacept is the only approved intravenous maintenance immunosuppressive therapy which provides the benefit of glomerular filtration rate preservation, but it was associated with a higher risk of acute rejection and post-transplant lymphoproliferative disorder. Bortezomib may help decrease donor-specific antibody levels, but there are limited data to support its use for desensitization or rejection. Eculizumab may help in antibody-mediated rejection in some cases but has not shown promising long-term effects in high-risk individuals. Newer agents have been continuously tested for improved efficacy and safety. SUMMARY Transplantation is the standard of care for end-stage renal disease patients, but we still have a long way to go, as we need to improve long-term outcomes. The manipulation of the immune system is a delicate undertaking, with risks of adverse events; therefore, risk versus benefit needs to be carefully evaluated and treatment needs to be individualized.
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Pilat N, Klaus C, Schwarz C, Hock K, Oberhuber R, Schwaiger E, Gattringer M, Ramsey H, Baranyi U, Zelger B, Brandacher G, Wrba F, Wekerle T. Rapamycin and CTLA4Ig synergize to induce stable mixed chimerism without the need for CD40 blockade. Am J Transplant 2015; 15:1568-79. [PMID: 25783859 DOI: 10.1111/ajt.13154] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 11/12/2014] [Accepted: 11/30/2014] [Indexed: 01/25/2023]
Abstract
The mixed chimerism approach achieves donor-specific tolerance in organ transplantation, but clinical use is inhibited by the toxicities of current bone marrow (BM) transplantation (BMT) protocols. Blocking the CD40:CD154 pathway with anti-CD154 monoclonal antibodies (mAbs) is exceptionally potent in inducing mixed chimerism, but these mAbs are clinically not available. Defining the roles of donor and recipient CD40 in a murine allogeneic BMT model, we show that CD4 or CD8 activation through an intact direct or CD4 T cell activation through the indirect pathway is sufficient to trigger BM rejection despite CTLA4Ig treatment. In the absence of CD4 T cells, CD8 T cell activation via the direct pathway, in contrast, leads to a state of split tolerance. Interruption of the CD40 signals in both the direct and indirect pathway of allorecognition or lack of recipient CD154 is required for the induction of chimerism and tolerance. We developed a novel BMT protocol that induces mixed chimerism and donor-specific tolerance to fully mismatched cardiac allografts relying on CD28 costimulation blockade and mTOR inhibition without targeting the CD40 pathway. Notably, MHC-mismatched/minor antigen-matched skin grafts survive indefinitely whereas fully mismatched grafts are rejected, suggesting that non-MHC antigens cause graft rejection and split tolerance.
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Affiliation(s)
- N Pilat
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
| | - C Klaus
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
| | - C Schwarz
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
| | - K Hock
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
| | - R Oberhuber
- Department of Visceral, Transplant, and Thoracic Surgery, Center of Operative Medicine, Innsbruck Medical University, Austria
| | - E Schwaiger
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
| | - M Gattringer
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
| | - H Ramsey
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
| | - U Baranyi
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
| | - B Zelger
- Institute of Pathology, Medical University of Innsbruck, Austria
| | - G Brandacher
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD
| | - F Wrba
- Institute of Clinical Pathology, Medical University of Vienna, Austria
| | - T Wekerle
- Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria
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40
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Cellular and molecular targeting for nanotherapeutics in transplantation tolerance. Clin Immunol 2015; 160:14-23. [PMID: 25805659 DOI: 10.1016/j.clim.2015.03.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 02/23/2015] [Accepted: 03/03/2015] [Indexed: 11/21/2022]
Abstract
The induction of donor-specific tolerance to transplanted cells and organs, while preserving immune function as a whole, remains a highly sought after and elusive strategy for overcoming transplant rejection. Tolerance necessitates modulating a diverse array of cell types that recognize and respond to alloantigens, including antigen presenting cells and T lymphocytes. Nanotherapeutic strategies that employ cellular and biomaterial engineering represent an emerging technology geared towards the goal of inducing transplant tolerance. Nanocarriers offer a platform for delivering antigens of interest to specific cell types in order to achieve tolerogenic antigen presentation. Furthermore, the technologies also provide an opportunity for local immunomodulation at the graft site. Nanocarriers delivering a combination of antigens and immunomodulating agents, such as rapamycin, provide a unique technology platform with the potential to enhance outcomes for the induction of transplant tolerance.
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41
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Abstract
BACKGROUND CTLA-4 immunoglobulin fusion proteins (CTLA4-Ig) suppress immune reactions by blocking the T-cell costimulatory CD28-CD80-86 pathway and are used in clinical trials for diseases featuring exaggerated T-cell reactivity including autoimmune diseases and allograft rejection. However, because CTLA4-Ig has been suspected to interfere with T regulatory (Treg) cell homeostasis and function, recently, substantial concerns on CTLA4-Ig's potentially antitolerogenic effects have been raised. METHODS We tested immunoregulatory CTLA4-Ig explicitly for its effect on Treg cell numbers, frequencies and function in an in vitro murine major histocompatibility complex mismatched setting using C57BL/6 bone marrow-derived dendritic cells as stimulators of allogeneic Balb/c Foxp3 T cells, which allowed for tracing Treg cells in a straightforward fashion. RESULTS The presence of CTLA4-Ig in mixed leukocyte reactions-while dampening the global proliferative response of allostimulated Balb/c T cells-resulted in a relative increase of the frequency of thymus-derived CD4CD25Foxp3 Treg cells with intact suppressive activity. This relative increase was caused by a selective inhibitory effect of CTLA4-Ig on proliferating conventional T cells, whereas the proliferative capacity of Treg cells in cell cultures remained unaffected. Additionally, in the presence of CTLA4-Ig, the frequency of apoptosis was decreased in these cells. CONCLUSION Our findings unequivocally demonstrate that CTLA4-Ig does not negatively affect Treg cell frequencies and function in vitro.
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Park SJ, Lee JS, Kwon B, Cho HR. Integration of the Innate and Adaptive Immunity by CD137-CD137L Bidirectional Signals: Implications in Allograft Rejection. KOREAN JOURNAL OF TRANSPLANTATION 2014. [DOI: 10.4285/jkstn.2014.28.3.113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Sang June Park
- Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, School of Biological Sciences4, University of Ulsan, Ulsan, Korea
- Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, School of Biological Sciences4, University of Ulsan, Ulsan, Korea
| | - Jong Soo Lee
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, School of Biological Sciences4, University of Ulsan, Ulsan, Korea
- Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, School of Biological Sciences4, University of Ulsan, Ulsan, Korea
| | - Byungsuk Kwon
- Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, School of Biological Sciences4, University of Ulsan, Ulsan, Korea
| | - Hong Rae Cho
- Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, School of Biological Sciences4, University of Ulsan, Ulsan, Korea
- Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, School of Biological Sciences4, University of Ulsan, Ulsan, Korea
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Hock K, Pilat N, Baranyi U, Mahr B, Gattringer M, Klaus C, Wekerle T. Donor CD4 T cells trigger costimulation blockade-resistant donor bone marrow rejection through bystander activation requiring IL-6. Am J Transplant 2014; 14:2011-22. [PMID: 25100658 DOI: 10.1111/ajt.12823] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 04/22/2014] [Accepted: 05/07/2014] [Indexed: 01/25/2023]
Abstract
Bone marrow (BM) transplantation under costimulation blockade induces chimerism and tolerance. Cotransplantation of donor T cells (contained in substantial numbers in mobilized peripheral blood stem cells and donor lymphocyte infusions) together with donor BM paradoxically triggers rejection of donor BM through undefined mechanisms. Here, nonmyeloablatively irradiated C57BL/6 recipients simultaneously received donor BM (BALB/c) and donor T cells under costimulation blockade (anti-CD154 and CTLA4Ig). Donor CD4, but not CD8 cells, triggered natural killer-independent donor BM rejection which was associated with increased production of IL-6, interferon gamma (IFN-γ) and IL-17A. BM rejection was prevented through neutralization of IL-6, but not of IFN-γ or IL-17A. IL-6 counteracted the antiproliferative effect of anti-CD154 in vitro. Rapamycin and anti-lymphocyte function-associated antigen 1 negated this effect of IL-6 in vitro and prevented BM rejection in vivo. Simultaneous cotransplantation of (BALB/cxB6)F1, recipient or irradiated donor CD4 cells, or late transfer of donor CD4 cells did not lead to BM rejection, whereas cotransplantation of third party CD4 cells did. Transferred donor CD4 cells became activated, rapidly underwent apoptosis and triggered activation and proliferation of recipient T cells. Collectively, these results provide evidence that donor T cells recognizing the recipient as allogeneic lead to the release of IL-6, which abolishes the effect of anti-CD154, triggering donor BM rejection through bystander activation.
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Affiliation(s)
- K Hock
- Department of Surgery, Medical University of Vienna, Vienna, Austria
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44
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Abstract
Advances in vascularized composite allotransplantation over the last decade have achieved significant milestones in basic science and translational research, as well as clinically with highly encouraging functional and immunologic outcomes. However, certain immunologic challenges remain. In particular, although tolerance has been induced to nearly all components of a hand allograft in experimental models, the skin component may still be subject to acute rejection episodes. Currently, conventional immunosuppressive protocols have been successful at preventing allograft loss; however, they have not prevented episodes of acute skin rejection. Furthermore, the profound side effect profile of the life-long, high-dose, multidrug immunosuppression regimen that is necessary to maintain a viable graft alters the risk to benefit ratio of this non-life-saving procedure. Therefore, there must be a concerted effort in the scientific community to develop novel protocols to either minimize immunosuppression or to induce tolerance to the allograft to promote the widespread application of this life-changing procedure.
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45
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Zhang X, Liu Y, Zhang G, Shi J, Zhang X, Zheng X, Jiang AT, Zhang ZX, Johnston N, Siu KS, Chen R, Lian D, Koos D, Quan D, Min WP. Synergic silencing of costimulatory molecules prevents cardiac allograft rejection. J Transl Med 2014; 12:142. [PMID: 24886282 PMCID: PMC4040111 DOI: 10.1186/1479-5876-12-142] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 04/28/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND While substantial progress has been made in blocking acute transplant rejection with the advent of immune suppressive drugs, chronic rejection, mediated primarily by recipient antigen presentation, remains a formidable problem in clinical transplantation. We hypothesized that blocking co-stimulatory pathways in the recipient by induction of RNA interference using small interference RNA (siRNA) expression vectors can prolong allogeneic heart graft survival. METHOD Vectors expressing siRNA specifically targeting CD40 and CD80 were prepared. Recipients (BALB/c mice) were treated with CD40 and/or CD80 siRNA expression vectors via hydrodynamic injection. Control groups were injected with a scrambled siRNA vector and sham treatment (PBS). After treatment, a fully MHC-mismatched (BALB/c to C57/BL6) heart transplantation was performed. RESULT Allogeneic heart graft survival (>100 days) was approximately 70% in the mice treated simultaneously with CD40 and CD80 siRNA expression vectors with overall reduction in lymphocyte interstitium infiltration, vascular obstruction, and edema. Hearts transplanted into CD40 or CD80 siRNA vector-treated recipients had an increased graft survival time compared to negative control groups, but did not survive longer than 40 days. In contrast, allogenic hearts transplanted into recipients treated with scrambled siRNA vector and PBS stopped beating within 10-16 days. Real-time PCR (RT-PCR) and flow cytometric analysis showed an upregulation of FoxP3 expression in spleen lymphocytes and a concurrent downregulation of CD40 and CD80 expression in splenic dendritic cells of siRNA-treated mice. Functional suppressive activity of splenic dendritic cells (DCs) isolated from tolerant recipients was demonstrated in a mixed lymphocyte reaction (MLR). Furthermore, DCs isolated from CD40- and CD80-treated recipients promoted CD4+CD25+FoxP3+ regulatory T cell differentiation in vitro. CONCLUSION This study demonstrates that the simultaneous silencing of CD40 and CD80 genes has synergistic effects in preventing allograft rejection, and may therefore have therapeutic potential in clinical transplantation.
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Affiliation(s)
- Xusheng Zhang
- Department of Surgery, Pathology, and Ocology, University of Western Ontario, London, Canada
- Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada
| | - Yanling Liu
- Jiangxi Academy of Medical Sciences, The First Affiliated Hospital, and Institute of Immunotherapy of Nanchang University, Nanchang, China
| | - Guangfeng Zhang
- Department of Surgery, Pathology, and Ocology, University of Western Ontario, London, Canada
- Department of Rheumatology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangdong, China
| | - Jun Shi
- Jiangxi Academy of Medical Sciences, The First Affiliated Hospital, and Institute of Immunotherapy of Nanchang University, Nanchang, China
| | - Xiao Zhang
- Department of Rheumatology, Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangdong, China
| | - Xiufen Zheng
- Department of Surgery, Pathology, and Ocology, University of Western Ontario, London, Canada
| | - Alex T Jiang
- Department of Surgery, Pathology, and Ocology, University of Western Ontario, London, Canada
| | - Zhu-Xu Zhang
- Department of Surgery, Pathology, and Ocology, University of Western Ontario, London, Canada
- Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada
| | - Nathan Johnston
- Department of Surgery, Pathology, and Ocology, University of Western Ontario, London, Canada
| | - King Sun Siu
- Department of Surgery, Pathology, and Ocology, University of Western Ontario, London, Canada
| | - Ruiqi Chen
- Department of Surgery, Pathology, and Ocology, University of Western Ontario, London, Canada
| | - Dameng Lian
- Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada
| | | | - Douglas Quan
- Department of Surgery, Pathology, and Ocology, University of Western Ontario, London, Canada
- Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada
| | - Wei-Ping Min
- Department of Surgery, Pathology, and Ocology, University of Western Ontario, London, Canada
- Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada
- Jiangxi Academy of Medical Sciences, The First Affiliated Hospital, and Institute of Immunotherapy of Nanchang University, Nanchang, China
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46
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Dugast E, Chesneau M, Soulillou JP, Brouard S. Biomarkers and possible mechanisms of operational tolerance in kidney transplant patients. Immunol Rev 2014; 258:208-17. [DOI: 10.1111/imr.12156] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Emilie Dugast
- INSERM UMR 1064; Nantes France
- Centaure; Nantes France
| | - Mélanie Chesneau
- INSERM UMR 1064; Nantes France
- Université de Nantes; Nantes France
| | - Jean-Paul Soulillou
- INSERM UMR 1064; Nantes France
- Centaure; Nantes France
- CHU de Nantes; Nantes France
- Université de Nantes; Nantes France
| | - Sophie Brouard
- INSERM UMR 1064; Nantes France
- Centaure; Nantes France
- CHU de Nantes; Nantes France
- Université de Nantes; Nantes France
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47
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Abstract
T cell activation is a key event in the adaptive immune response and vital to the generation of both cellular and humoral immunity. Activation is required not only for effective CD4 T cell responses but also to provide help for B cells and the generation of cytotoxic T cell responses. Unsurprisingly, impaired T cell activation results in infectious pathology, whereas dysregulated activation can result in autoimmunity. The decision to activate is therefore tightly regulated and the CD28/CTLA-4 pathway represents this apical decision point at the molecular level. In particular, CTLA-4 (CD152) is an essential checkpoint control for autoimmunity; however, the molecular mechanism(s) by which CTLA-4 achieves its regulatory function are not well understood, especially how it functionally intersects with the CD28 pathway. In this chapter, we review the established molecular and cellular concepts relating to CD28 and CTLA-4 biology, and attempt to integrate these by discussing the transendocytosis of ligands as a new model of CTLA-4 function.
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Affiliation(s)
- Blagoje Soskic
- School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
| | | | - Tiezheng Hou
- UCL Institute of Immunity and Transplantation, Royal Free Campus, London, United Kingdom
| | - David M Sansom
- UCL Institute of Immunity and Transplantation, Royal Free Campus, London, United Kingdom.
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48
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49
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Davidson MG, Alonso MN, Kenkel JA, Suhoski MM, González JC, Yuan R, Engleman EG. In vivo T cell activation induces the formation of CD209(+) PDL-2(+) dendritic cells. PLoS One 2013; 8:e76258. [PMID: 24098455 PMCID: PMC3788745 DOI: 10.1371/journal.pone.0076258] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 08/21/2013] [Indexed: 01/06/2023] Open
Abstract
Two critical functions of dendritic cells (DC) are to activate and functionally polarize T cells. Activated T cells can, in turn, influence DC maturation, although their effect on de novo DC development is poorly understood. Here we report that activation of T cells in mice, with either an anti-CD3 antibody or super antigen, drives the rapid formation of CD209(+)CD11b(+)CD11c(+) MHC II(+) DC from monocytic precursors (Mo-DC). GM-CSF is produced by T cells following activation, but surprisingly, it is not required for the formation of CD209(+) Mo-DC. CD40L, however, is critical for the full induction of Mo-DC following T cell activation. T cell induced CD209(+) Mo-DC are comparable to conventional CD209(-) DC in their ability to stimulate T cell proliferation. However, in contrast to conventional CD209(-) DC, CD209(+) Mo-DC fail to effectively polarize T cells, as indicated by a paucity of T cell cytokine production. The inability of CD209(+) Mo-DC to polarize T cells is partly explained by increased expression of PDL-2, since blockade of this molecule restores some polarizing capacity to the Mo-DC. These findings expand the range of signals capable of driving Mo-DC differentiation in vivo beyond exogenous microbial factors to include endogenous factors produced following T cell activation.
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Affiliation(s)
- Matthew G. Davidson
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California, United States of America
| | - Michael N. Alonso
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California, United States of America
| | - Justin A. Kenkel
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California, United States of America
| | - Megan M. Suhoski
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California, United States of America
| | - Joseph C. González
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California, United States of America
| | - Robert Yuan
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California, United States of America
| | - Edgar G. Engleman
- Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California, United States of America
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50
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Abstract
Large animal models have long served as the proving grounds for advances in transplantation, bridging the gap between inbred mouse experimentation and human clinical trials. Although a variety of species have been and continue to be used, the emergence of highly targeted biologic- and antibody-based therapies has required models to have a high degree of homology with humans. Thus, the nonhuman primate has become the model of choice in many settings. This article will provide an overview of nonhuman primate models of transplantation. Issues of primate genetics and care will be introduced, and a brief overview of technical aspects for various transplant models will be discussed. Finally, several prominent immunosuppressive and tolerance strategies used in primates will be reviewed.
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Affiliation(s)
- Douglas J Anderson
- Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia 30322
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