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Jin X, Pirenne J, Vos R, Hooft C, Kaes J, Van Slambrouck J, Kortleven P, Vandervelde C, Beeckmans H, Kerckhof P, Carlon MS, Van Raemdonck D, Looney MR, Vanaudenaerde BM, Ceulemans LJ. Donor-Specific Blood Transfusion in Lung Transplantation. Transpl Int 2024; 37:12822. [PMID: 39553536 PMCID: PMC11565953 DOI: 10.3389/ti.2024.12822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 10/15/2024] [Indexed: 11/19/2024]
Abstract
Lung transplantation is still hindered by a high rate of chronic rejection necessitating profound immunosuppression with its associated complications. Donor-specific blood transfusion is a pre-transplant strategy aimed at improving graft acceptance. In contrast with standard stored blood or donor-specific regulatory T cells transfusions, this approach utilizes fresh whole blood from the donor prior to allograft transplantation, encompassing all cell types and plasma. The precise mechanisms underlying donor-specific blood transfusion-induced tolerance remain incompletely understood. Associations with regulatory/helper T cells, modulation of mononuclear phagocytic cells or microchimerism have been suggested. While numerous (pre-)clinical studies have explored its application in solid organ transplants like liver, kidney, and intestine, limited attention has been given to the setting of lung transplantation. This comprehensive review summarizes existing knowledge on the mechanisms and outcomes of donor-specific blood transfusion in solid organ transplants both in preclinical and clinical settings. We also address the potential benefits and risks associated with donor-specific blood transfusion in the field of lung transplantation, offering insights into future research directions.
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Affiliation(s)
- Xin Jin
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Jacques Pirenne
- Department of Microbiology, Immunology and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Robin Vos
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Charlotte Hooft
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Janne Kaes
- Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven), KU Leuven, Leuven, Belgium
| | - Jan Van Slambrouck
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Phéline Kortleven
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Christelle Vandervelde
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Hanne Beeckmans
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Pieterjan Kerckhof
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Marianne S. Carlon
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Dirk Van Raemdonck
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Mark R. Looney
- Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, United States
- Department of Laboratory Medicine, University of California, San Francisco (UCSF), San Francisco, CA, United States
| | - Bart M. Vanaudenaerde
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Laurens J. Ceulemans
- Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
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Zhang J, Wei X, Zhang Q, Jiao X, Li K, Geng M, Cao Y, Wang D, Cheng J, Yang J. Fish Uses CTLA-4 Immune Checkpoint to Suppress mTORC1-Controlled T-Cell Glycolysis and Immunity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1113-1128. [PMID: 38363204 DOI: 10.4049/jimmunol.2300599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 01/26/2024] [Indexed: 02/17/2024]
Abstract
As an immune checkpoint, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) suppresses the activation, proliferation, and effector function of T cells, thus preventing an overexuberant response and maintaining immune homeostasis. However, whether and how this immune checkpoint functions in early vertebrates remains unknown. In the current study, using a Nile tilapia (Oreochromis niloticus) model, we investigated the suppression of T cell response by CTLA-4 in bony fish. Tilapia CTLA-4 is constitutively expressed in lymphoid tissues, and its mRNA and protein expression in lymphocytes are upregulated following PHA stimulation or Edwardsiella piscicida infection. Blockade of CTLA-4 signaling enhanced T cell activation and proliferation but inhibited activation-induced T cell apoptosis, indicating that CTLA-4 negatively regulated T cell activation. In addition, blocking CTLA-4 signaling in vivo increased the differentiation potential and cytotoxicity of T cells, resulting in an enhanced T cell response during E. piscicida infection. Tilapia CTLA-4 competitively bound the B7.2/CD86 molecule with CD28, thus antagonizing the CD28-mediated costimulatory signal of T cell activation. Furthermore, inhibition of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, c-Myc, or glycolysis markedly impaired the CTLA-4 blockade-enhanced T cell response, suggesting that CTLA-4 suppressed the T cell response of tilapia by inhibiting mTORC1/c-Myc axis-controlled glycolysis. Overall, the findings indicate a detailed mechanism by which CTLA-4 suppresses T cell immunity in tilapia; therefore, we propose that early vertebrates have evolved sophisticated mechanisms coupling immune checkpoints and metabolic reprogramming to avoid an overexuberant T cell response.
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Affiliation(s)
- Jiansong Zhang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, China
| | - Xiumei Wei
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, China
| | - Qian Zhang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, China
| | - Xinying Jiao
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, China
| | - Kang Li
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, China
| | - Ming Geng
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, China
| | - Yi Cao
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, China
| | - Ding Wang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, China
| | - Jie Cheng
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, China
| | - Jialong Yang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
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Kitchens WH, Larsen CP, Badell IR. Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future. Kidney Int Rep 2023; 8:2529-2545. [PMID: 38106575 PMCID: PMC10719580 DOI: 10.1016/j.ekir.2023.08.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/01/2023] [Accepted: 08/28/2023] [Indexed: 12/19/2023] Open
Abstract
Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization.
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Affiliation(s)
- William H. Kitchens
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Christian P. Larsen
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - I. Raul Badell
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
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Alhejailan RS, Garoffolo G, Raveendran VV, Pesce M. Cells and Materials for Cardiac Repair and Regeneration. J Clin Med 2023; 12:jcm12103398. [PMID: 37240504 DOI: 10.3390/jcm12103398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/05/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
After more than 20 years following the introduction of regenerative medicine to address the problem of cardiac diseases, still questions arise as to the best cell types and materials to use to obtain effective clinical translation. Now that it is definitively clear that the heart does not have a consistent reservoir of stem cells that could give rise to new myocytes, and that there are cells that could contribute, at most, with their pro-angiogenic or immunomodulatory potential, there is fierce debate on what will emerge as the winning strategy. In this regard, new developments in somatic cells' reprogramming, material science and cell biophysics may be of help, not only for protecting the heart from the deleterious consequences of aging, ischemia and metabolic disorders, but also to boost an endogenous regeneration potential that seems to be lost in the adulthood of the human heart.
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Affiliation(s)
- Reem Saud Alhejailan
- Cell Biology Department, King's Faisal Specialist Hospital & Research Center, Riyadh 11564, Saudi Arabia
| | - Gloria Garoffolo
- Unità di Ingegneria Tissutale Cardiovascolare, Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy
| | - Vineesh Vimala Raveendran
- Cell Biology Department, King's Faisal Specialist Hospital & Research Center, Riyadh 11564, Saudi Arabia
| | - Maurizio Pesce
- Unità di Ingegneria Tissutale Cardiovascolare, Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy
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5
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Wang X, Wang K, Yu M, Velluto D, Hong X, Wang B, Chiu A, Melero-Martin JM, Tomei AA, Ma M. Engineered immunomodulatory accessory cells improve experimental allogeneic islet transplantation without immunosuppression. SCIENCE ADVANCES 2022; 8:eabn0071. [PMID: 35867788 PMCID: PMC9307254 DOI: 10.1126/sciadv.abn0071] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 06/08/2022] [Indexed: 05/05/2023]
Abstract
Islet transplantation has been established as a viable treatment modality for type 1 diabetes. However, the side effects of the systemic immunosuppression required for patients often outweigh its benefits. Here, we engineer programmed death ligand-1 and cytotoxic T lymphocyte antigen 4 immunoglobulin fusion protein-modified mesenchymal stromal cells (MSCs) as accessory cells for islet cotransplantation. The engineered MSCs (eMSCs) improved the outcome of both syngeneic and allogeneic islet transplantation in diabetic mice and resulted in allograft survival for up to 100 days without any systemic immunosuppression. Immunophenotyping revealed reduced infiltration of CD4+ or CD8+ T effector cells and increased infiltration of T regulatory cells within the allografts cotransplanted with eMSCs compared to controls. The results suggest that the eMSCs can induce local immunomodulation and may be applicable in clinical islet transplantation to reduce or minimize the need of systemic immunosuppression and ameliorate its negative impact.
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Affiliation(s)
- Xi Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Kai Wang
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Ming Yu
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Diana Velluto
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Xuechong Hong
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Bo Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Alan Chiu
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Juan M. Melero-Martin
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Alice A. Tomei
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
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Kanzawa T, Tokita D, Saiga K, Yamakawa T, Ishigooka H, Fukuda H, Katsumata H, Miyairi S, Ishii R, Hirai T, Imai T, Okumi M, Tanabe K. Role of Fractalkine-CX3CR1 Axis in Acute Rejection of Mouse Heart Allografts Subjected to Ischemia Reperfusion Injury. Transpl Int 2022; 35:10157. [PMID: 35185378 PMCID: PMC8842273 DOI: 10.3389/ti.2022.10157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/10/2022] [Indexed: 11/24/2022]
Abstract
Transplantation outcomes are affected by the increase in rejection associated with ischemia reperfusion injury (IRI). Fractalkine (FKN), a chemokine for recruitment of CX3CR1+ leukocytes, contributes to the pathogenesis of various inflammatory diseases. Herein, we evaluated the importance of the FKN-CX3CR1 axis during IRI-related rejections using a mouse heterotopic heart transplantation model. FKN expression and graft survival was compared between wild-type C57BL/6 recipients transplanted with BALB/c hearts preserved for 8 (WT-IRI) and 0.5 h (WT-control) at 4°C. Graft survival of WT-IRI was shorter than that of WT-control. FKN was expressed on the vascular endothelium in WT-IRI allografts, but minimally in WT-control. The role of the FKN-CX3CR1 axis in IRI-related rejection was directly investigated using the transplant model with CX3CR1-deficient recipients (CX3CR1 KO-IRI) or treatment with anti-mouse FKN monoclonal antibodies. Graft survival of CX3CR1 KO-IRI was longer than that of WT-IRI; antibody treatment prolonged graft survival. The contribution of CX3CR1+ monocytes to IRI-related rejection was evaluated by adoptive transfer to CX3CR1 KO-IRI. Adoptive transfer of CX3CR1+ monocytes attenuated the effect of prolonged graft survival in CX3CR1 KO-IRI. Overall, the FKN-CX3CR1 axis plays a major role during IRI-related rejection; its blockade has the potential to improve the outcomes of deceased donor transplantation.
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Affiliation(s)
- Taichi Kanzawa
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Daisuke Tokita
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
- Clinical and Academic Research Promotion Center, Tokyo Women’s Medical University, Tokyo, Japan
- *Correspondence: Daisuke Tokita, ; Kan Saiga,
| | - Kan Saiga
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
- Department of Urology, Jyoban Hospital of Tokiwa Foundation, Fukushima, Japan
- *Correspondence: Daisuke Tokita, ; Kan Saiga,
| | - Takafumi Yamakawa
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | | | - Hironori Fukuda
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Haruki Katsumata
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Satoshi Miyairi
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Rumi Ishii
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Toshihito Hirai
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | | | - Masayoshi Okumi
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
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Galow AM, Goldammer T, Hoeflich A. Xenogeneic and Stem Cell-Based Therapy for Cardiovascular Diseases: Genetic Engineering of Porcine Cells and Their Applications in Heart Regeneration. Int J Mol Sci 2020; 21:ijms21249686. [PMID: 33353186 PMCID: PMC7766969 DOI: 10.3390/ijms21249686] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/11/2020] [Accepted: 12/15/2020] [Indexed: 12/25/2022] Open
Abstract
Cardiovascular diseases represent a major health concern worldwide with few therapy options for ischemic injuries due to the limited regeneration potential of affected cardiomyocytes. Innovative cell replacement approaches could facilitate efficient regenerative therapy. However, despite extensive attempts to expand primary human cells in vitro, present technological limitations and the lack of human donors have so far prevented their broad clinical use. Cell xenotransplantation might provide an ethically acceptable unlimited source for cell replacement therapies and bridge the gap between waiting recipients and available donors. Pigs are considered the most suitable candidates as a source for xenogeneic cells and tissues due to their anatomical and physiological similarities with humans. The potential of porcine cells in the field of stem cell-based therapy and regenerative medicine is under intensive investigation. This review outlines the current progress and highlights the most promising approaches in xenogeneic cell therapy with a focus on the cardiovascular system.
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Affiliation(s)
- Anne-Marie Galow
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology, 18196 Dummerstorf, Germany; (T.G.); (A.H.)
- Correspondence: ; Tel.: +49-38208-68-723
| | - Tom Goldammer
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology, 18196 Dummerstorf, Germany; (T.G.); (A.H.)
- Molecular Biology and Fish Genetics Unit, Faculty of Agriculture and Environmental Sciences, University of Rostock, 18059 Rostock, Germany
| | - Andreas Hoeflich
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology, 18196 Dummerstorf, Germany; (T.G.); (A.H.)
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8
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Ordikhani F, Pothula V, Sanchez-Tarjuelo R, Jordan S, Ochando J. Macrophages in Organ Transplantation. Front Immunol 2020; 11:582939. [PMID: 33329555 PMCID: PMC7734247 DOI: 10.3389/fimmu.2020.582939] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
Current immunosuppressive therapy has led to excellent short-term survival rates in organ transplantation. However, long-term graft survival rates are suboptimal, and a vast number of allografts are gradually lost in the clinic. An increasing number of animal and clinical studies have demonstrated that monocytes and macrophages play a pivotal role in graft rejection, as these mononuclear phagocytic cells recognize alloantigens and trigger an inflammatory cascade that activate the adaptive immune response. Moreover, recent studies suggest that monocytes acquire a feature of memory recall response that is associated with a potent immune response. This form of memory is called “trained immunity,” and it is retained by mechanisms of epigenetic and metabolic changes in innate immune cells after exposure to particular ligands, which have a direct impact in allograft rejection. In this review article, we highlight the role of monocytes and macrophages in organ transplantation and summarize therapeutic approaches to promote tolerance through manipulation of monocytes and macrophages. These strategies may open new therapeutic opportunities to increase long-term transplant survival rates in the clinic.
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Affiliation(s)
- Farideh Ordikhani
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Venu Pothula
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Rodrigo Sanchez-Tarjuelo
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Stefan Jordan
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Jordi Ochando
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
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9
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Giannis D, Moris D, Cendales LC. Costimulation Blockade in Vascularized Composite Allotransplantation. Front Immunol 2020; 11:544186. [PMID: 33042138 PMCID: PMC7527523 DOI: 10.3389/fimmu.2020.544186] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/19/2020] [Indexed: 12/14/2022] Open
Abstract
Vascular composite allotransplantation (VCA) is a field under research and has emerged as an alternative option for the repair of severe disfiguring defects that result from infections or traumatic amputation in a selected group of patients. VCA is performed in centers with appropriate expertise, experience and adequate resources to effectively manage the complexity and complications of this treatment. Lifelong immunosuppressive therapy, immunosuppression associated complications, and the effects of the host immune response in the graft are major concerns in VCA. VCA is considered a quality of life transplant and the risk-benefit ratio is dissimilar to life saving transplants. Belatacept seems a promising drug that prolongs patient and graft survival in kidney transplantation and it could also be an alternative approach to VCA immunosuppression. In this review, we are summarizing current literature about the role of costimulation blockade, with a focus on belatacept in VCA.
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Affiliation(s)
- Dimitrios Giannis
- Institute of Health Innovations and Outcomes Research, Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Dimitrios Moris
- Duke Surgery, Duke University Medical Center, Durham, NC, United States
| | - Linda C. Cendales
- Duke Surgery, Duke University Medical Center, Durham, NC, United States
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10
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Yi Z, Keung KL, Li L, Hu M, Lu B, Nicholson L, Jimenez-Vera E, Menon MC, Wei C, Alexander S, Murphy B, O’Connell PJ, Zhang W. Key driver genes as potential therapeutic targets in renal allograft rejection. JCI Insight 2020; 5:136220. [PMID: 32634125 PMCID: PMC7455082 DOI: 10.1172/jci.insight.136220] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/24/2020] [Indexed: 01/09/2023] Open
Abstract
Acute rejection (AR) in renal transplantation is an established risk factor for reduced allograft survival. Molecules with regulatory control among immune pathways of AR that are inadequately suppressed, despite standard-of-care immunosuppression, could serve as important targets for therapeutic manipulation to prevent rejection. Here, an integrative, network-based computational strategy incorporating gene expression and genotype data of human renal allograft biopsy tissue was applied, to identify the master regulators - the key driver genes (KDGs) - within dysregulated AR pathways. A 982-meta-gene signature with differential expression in AR versus non-AR was identified from a meta-analysis of microarray data from 735 human kidney allograft biopsy samples across 7 data sets. Fourteen KDGs were derived from this signature. Interrogation of 2 publicly available databases identified compounds with predicted efficacy against individual KDGs or a key driver-based gene set, respectively, which could be repurposed for AR prevention. Minocycline, a tetracycline antibiotic, was chosen for experimental validation in a murine cardiac allograft model of AR. Minocycline attenuated the inflammatory profile of AR compared with controls and when coadministered with immunosuppression prolonged graft survival. This study demonstrates that a network-based strategy, using expression and genotype data to predict KDGs, assists target prioritization for therapeutics in renal allograft rejection.
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Affiliation(s)
- Zhengzi Yi
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Karen L. Keung
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
- Department of Nephrology, Prince of Wales Hospital, Sydney, Australia
| | - Li Li
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Sema4, Stamford, Connecticut, Connecticut, USA
| | - Min Hu
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Bo Lu
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
| | - Leigh Nicholson
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
| | - Elvira Jimenez-Vera
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
| | - Madhav C. Menon
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Chengguo Wei
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Stephen Alexander
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
- Nephrology Department, The Children’s Hospital at Westmead, Sydney, Australia
| | - Barbara Murphy
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Philip J. O’Connell
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
- Department of Nephrology, Westmead Hospital, Sydney, Australia
| | - Weijia Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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11
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Schönberg A, Hamdorf M, Bock F. Immunomodulatory Strategies Targeting Dendritic Cells to Improve Corneal Graft Survival. J Clin Med 2020; 9:E1280. [PMID: 32354200 PMCID: PMC7287922 DOI: 10.3390/jcm9051280] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/08/2020] [Accepted: 04/21/2020] [Indexed: 12/16/2022] Open
Abstract
Even though the cornea is regarded as an immune-privileged tissue, transplantation always comes with the risk of rejection due to mismatches between donor and recipient. It is common sense that an alternative to corticosteroids as the current gold standard for treatment of corneal transplantation is needed. Since blood and lymphatic vessels have been identified as a severe risk factor for corneal allograft survival, much research has focused on vessel regression or inhibition of hem- and lymphangiogenesis in general. However, lymphatic vessels have been identified as required for the inflammation's resolution. Therefore, targeting other players of corneal engraftment could reveal new therapeutic strategies. The establishment of a tolerogenic microenvironment at the graft site would leave the recipient with the ability to manage pathogenic conditions independent from transplantation. Dendritic cells (DCs) as the central player of the immune system represent a target that allows the induction of tolerogenic mechanisms by many different strategies. These strategies are reviewed in this article with regard to their success in corneal transplantation.
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Affiliation(s)
- Alfrun Schönberg
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (M.H.)
| | - Matthias Hamdorf
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (M.H.)
| | - Felix Bock
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (M.H.)
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany
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12
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Oh BC, Furtmüller GJ, Fryer ML, Guo Y, Messner F, Krapf J, Schneeberger S, Cooney DS, Lee WPA, Raimondi G, Brandacher G. Vascularized composite allotransplantation combined with costimulation blockade induces mixed chimerism and reveals intrinsic tolerogenic potential. JCI Insight 2020; 5:128560. [PMID: 32271163 DOI: 10.1172/jci.insight.128560] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 03/04/2020] [Indexed: 12/14/2022] Open
Abstract
Vascularized composite allotransplantation (VCA) has become a valid therapeutic option to restore form and function after devastating tissue loss. However, the need for high-dose multidrug immunosuppression to maintain allograft survival is still hampering more widespread application of VCA. In this study, we investigated the immunoregulatory potential of costimulation blockade (CoB; CTLA4-Ig and anti-CD154 mAb) combined with nonmyeoablative total body irradiation (TBI) to promote allograft survival of VCA in a fully MHC-mismatched mouse model of orthotopic hind limb transplantation. Compared with untreated controls (median survival time [MST] 8 days) and CTLA4-Ig treatment alone (MST 17 days), CoB treatment increased graft survival (MST 82 days), and the addition of nonmyeloablative TBI led to indefinite graft survival (MST > 210 days). Our analysis suggests that VCA-derived BM induced mixed chimerism in animals treated with CoB and TBI + CoB, promoting gradual deletion of alloreactive T cells as the underlying mechanism of long-term allograft survival. Acceptance of donor-matched secondary skin grafts, decreased ex vivo T cell responsiveness, and increased graft-infiltrating Tregs further indicated donor-specific tolerance induced by TBI + CoB. In summary, our data suggest that vascularized BM-containing VCAs are immunologically favorable grafts promoting chimerism induction and long-term allograft survival in the context of CoB.
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Affiliation(s)
- Byoung Chol Oh
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Georg J Furtmüller
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Madeline L Fryer
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Yinan Guo
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Hand and Microsurgery, Xiangya Hospital, Central South University, Hunan, China
| | - Franka Messner
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Visceral, Transplant and Thoracic Surgery, and
| | - Johanna Krapf
- Department of Plastic and Reconstructive Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Damon S Cooney
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - W P Andrew Lee
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Giorgio Raimondi
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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13
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Rachid O, Osman A, Abdi R, Haik Y. CTLA4-Ig (abatacept): a promising investigational drug for use in type 1 diabetes. Expert Opin Investig Drugs 2020; 29:221-236. [PMID: 32031422 DOI: 10.1080/13543784.2020.1727885] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of insulin-producing beta cells in the pancreas; it leads to the under or nonproduction of insulin. T1D is associated with numerous life-threatening micro- and macro-vascular complications and early deaths, hence the development of preventative strategies is a priority for research.Areas covered: The authors outline the drawbacks of available treatments for T1D and assess the three key strategies for prevention, including immunomodulatory therapies which hold the most potential. This article examines CTLA4-Ig and its efficacy and safety profiles. Finally, the pharmacokinetic parameters and pharmacodynamic markers of abatacept are shown in vivo and in clinical trials, guiding dosage regimen recommendations for future investigational studies.Expert opinion: Immunomodulation is one of the promising strategies for decelerating the progression of beta-cell destruction after the onset of T1D. It holds the advantage of specific immune modulation without systemic general immunosuppression. Preclinical and clinical studies have yielded promising data on the use of CTLA4-Ig in T1D. Variations in response to CTLA4-Ig might be partially explained by the existence of multiple T1D subtypes with varying baseline innate inflammatory/regulatory bias and the rate of C-peptide decline.
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Affiliation(s)
- Ousama Rachid
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Aisha Osman
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Reza Abdi
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Yousef Haik
- Sustainable Development, College of Science and Engineering, Hamad Bin Khalifa University, Doha, Qatar
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14
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Plenter RJ, Coulombe MG, Roybal HM, Lin CM, Gill RG, Zamora MR, Grazia TJ. C-kit-derived CD11b + cells are critical for cardiac allograft prolongation by autologous C-kit + progenitor cells. Cell Immunol 2020; 347:104023. [PMID: 31836133 DOI: 10.1016/j.cellimm.2019.104023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 11/06/2019] [Accepted: 11/25/2019] [Indexed: 10/25/2022]
Abstract
Autologous C-kit+ cells robustly prolong cardiac allografts. As C-kit+ cells can transdifferentiate to hematopoietic cells as well as non-hematopoietic cells, we aimed to clarify the class(es) of C-kit-derived cell(s) required for cardiac allograft prolongation. Autologous C-kit+ cells were administered post-cardiac transplantation and allografts were evaluated for C-kit+ inoculum-derived cells. Results suggested that alloimmunity was a major signal for trafficking of C-kit-derived cells to the allograft and demonstrated that C-kit+ inoculum-derived cells expressed CD11b early after transfer. Allograft survival studies with CD11b-DTR C-kit+ cells demonstrated a requirement for C-kit+-derived CD11b+ cells. Co-therapy studies demonstrated near complete abrogation of acute rejection with concomitant CTLA4-Ig therapy and no loss of prolongation in combination with Cyclosporine A. These results strongly implicate a C-kit-derived myeloid population as critical for allograft preservation and demonstrate the potential therapeutic application of autologous C-kit+ progenitor cells as calcineurin inhibitor-sparing agents and possibly as co-therapeutics for durable graft survival.
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Affiliation(s)
- R J Plenter
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA; Department of Surgery, University of Colorado, Aurora, CO, USA.
| | - M G Coulombe
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA; Department of Surgery, University of Colorado, Aurora, CO, USA.
| | - H M Roybal
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA.
| | - C M Lin
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA.
| | - R G Gill
- Department of Microbiology and Immunology, University of Colorado, Aurora, CO, USA; Department of Surgery, University of Colorado, Aurora, CO, USA.
| | - M R Zamora
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA.
| | - T J Grazia
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA; Department of Microbiology and Immunology, University of Colorado, Aurora, CO, USA; Division of Pulmonary Diseases, Section of Advanced Lung Disease and Lung Transplantation, Baylor University Medical Center, Dallas, TX, USA.
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15
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Zimmerer JM, Ringwald BA, Elzein SM, Avila CL, Warren RT, Abdel-Rasoul M, Bumgardner GL. Antibody-suppressor CD8+ T Cells Require CXCR5. Transplantation 2019; 103:1809-1820. [PMID: 30830040 PMCID: PMC6713619 DOI: 10.1097/tp.0000000000002683] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND We previously reported the novel activity of alloprimed CD8 T cells that suppress posttransplant alloantibody production. The purpose of the study is to investigate the expression and role of CXCR5 on antibody-suppressor CD8 T-cell function. METHODS C57BL/6 mice were transplanted with FVB/N hepatocytes. Alloprimed CD8 T cells were retrieved on day 7 from hepatocyte transplant recipients. Unsorted or flow-sorted (CXCR5CXCR3 and CXCR3CXCR5) alloprimed CD8 T-cell subsets were analyzed for in vitro cytotoxicity and capacity to inhibit in vivo alloantibody production following adoptive transfer into C57BL/6 or high alloantibody-producing CD8 knock out (KO) hepatocyte transplant recipients. Alloantibody titer was assessed in CD8 KO mice reconstituted with naive CD8 T cells retrieved from C57BL/6, CXCR5 KO, or CXCR3 KO mice. Antibody suppression by ovalbumin (OVA)-primed monoclonal OVA-specific t-cell receptor transgenic CD8+ T cells (OT-I) CXCR5 or CXCR3 CD8 T-cell subsets was also investigated. RESULTS Alloprimed CXCR5CXCR3CD8 T cells mediated in vitro cytotoxicity of alloprimed "self" B cells, while CXCR3CXCR5CD8 T cells did not. Only flow-sorted alloprimed CXCR5CXCR3CD8 T cells (not flow-sorted alloprimed CXCR3CXCR5CD8 T cells) suppressed alloantibody production and enhanced graft survival when transferred into transplant recipients. Unlike CD8 T cells from wild-type or CXCR3 KO mice, CD8 T cells from CXCR5 KO mice do not develop alloantibody-suppressor function. Similarly, only flow-sorted CXCR5CXCR3 (and not CXCR3CXCR5) OVA-primed OT-I CD8 T cells mediated in vivo suppression of anti-OVA antibody production. CONCLUSIONS These data support the conclusion that expression of CXCR5 by antigen-primed CD8 T cells is critical for the function of antibody-suppressor CD8 T cells.
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Affiliation(s)
- Jason M. Zimmerer
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - Bryce A. Ringwald
- Medical Student Research Program, The Ohio State University College of Medicine, Columbus, OH
| | - Steven M. Elzein
- Medical Student Research Program, The Ohio State University College of Medicine, Columbus, OH
| | - Christina L. Avila
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - Robert T. Warren
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | | | - Ginny L. Bumgardner
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
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16
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Schwarz C, Mahr B, Muckenhuber M, Wekerle T. Belatacept/CTLA4Ig: an update and critical appraisal of preclinical and clinical results. Expert Rev Clin Immunol 2018; 14:583-592. [PMID: 29874474 DOI: 10.1080/1744666x.2018.1485489] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The B7/CD28/CTLA4 signaling cascade is the most thoroughly studied costimulatory pathway and blockade with CTLA4Ig (abatacept) or its derivative belatacept has emerged as a valuable option for pharmacologic immune modulation. Several clinical studies have ultimately led to the approval of belatacept for immunosuppression in kidney transplant recipients. Areas covered: This review will discuss the immunological background of costimulation blockade and recent preclinical data and clinical results of CTLA4Ig/belatacept. Expert commentary: The development of belatacept is a major advance in clinical transplantation. However, in spite of promising results in preclinical and clinical trials, clinical use remains limited at present, in part due to increased rates of acute rejection. Recent efforts showing encouraging progress in refining such protocols might be a step toward harnessing the full potential of costimulation blockade-based immunosuppression.
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Affiliation(s)
- Christoph Schwarz
- a Division of General Surgery, Department of Surgery , Medical University of Vienna , Vienna , Austria.,b Section of Transplantation Immunology, Department of Surgery , Medical University of Vienna , Vienna , Austria
| | - Benedikt Mahr
- b Section of Transplantation Immunology, Department of Surgery , Medical University of Vienna , Vienna , Austria
| | - Moritz Muckenhuber
- b Section of Transplantation Immunology, Department of Surgery , Medical University of Vienna , Vienna , Austria
| | - Thomas Wekerle
- b Section of Transplantation Immunology, Department of Surgery , Medical University of Vienna , Vienna , Austria
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17
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Adams AB, Ford ML, Larsen CP. Costimulation Blockade in Autoimmunity and Transplantation: The CD28 Pathway. THE JOURNAL OF IMMUNOLOGY 2017; 197:2045-50. [PMID: 27591335 DOI: 10.4049/jimmunol.1601135] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 07/11/2016] [Indexed: 12/30/2022]
Abstract
T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. TCR signaling in the absence of costimulatory signals can lead to an abortive attempt at activation and subsequent anergy. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. The development of the fusion protein CTLA-4-Ig as an experimental and subsequent therapeutic tool is one of the major success stories in modern immunology. Abatacept and belatacept are clinically approved agents for the treatment of rheumatoid arthritis and renal transplantation, respectively. Future interventions may include selective CD28 blockade to block the costimulatory potential of CD28 while exploiting the coinhibitory effects of CTLA-4.
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Affiliation(s)
- Andrew B Adams
- Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322
| | - Mandy L Ford
- Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322
| | - Christian P Larsen
- Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322
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18
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Ye QX, Xu LH, Shi PJ, Xia T, Fang JP. Indoleamine 2,3-dioxygenase and inducible nitric oxide synthase mediate immune tolerance induced by CTLA4Ig and anti-CD154 hematopoietic stem cell transplantation in a sensitized mouse model. Exp Ther Med 2017; 14:1884-1891. [PMID: 28962099 PMCID: PMC5609130 DOI: 10.3892/etm.2017.4722] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 02/02/2017] [Indexed: 12/29/2022] Open
Abstract
Cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4Ig) and anti-cluster of differentiation 154 (anti-CD154) are able to block B7/CD28 and CD40/CD154 co-stimulatory signals in T cells. Additionally, they promote hematopoietic stem cell transplantation (HSCT) in sensitized recipients and are able to induce immune tolerance and complete hematopoietic reconstitution. Indoleamine 2, 3-dioxygenase (IDO) and nitric oxide (NO) have been implicated in T cell immune tolerance. The aim of the present report was to study the in vivo tolerogenic mechanisms by which CTLA4Ig and anti-CD154 induce transplantation survival in mice receiving HSCT. BALB/c mice were sensitized via splenocyte transfusion and pretreated with CTLA4Ig plus anti-CD154 on day-7. IDO and inducible nitric oxide synthase (iNOS) inhibitors were applied on days-7 to 0 and the mice were divided into 4 groups (n=10) and injected with IDO every other day. The mice were sacrificed on day 0, and splenocytes were separated to identify CD11c+ antigen-presenting cells, which were subsequently assessed for IDO expression and activity. The concentration of NO was tested using a nitrate reductase kit. Following the acceptance of allogeneic HSCT, mice were tested for homing and engraftment, as well as survival rate. Application of the IDO inhibitor increased the concentration of NO, whereas a decrease in NO resulted in increased IDO activity. Immune tolerance was abrogated in the presence of both IDO and iNOS inhibitors, whereas this effect was not observed with either compound alone. CTLA4Ig and anti-CD154 may induce immune tolerance by affecting the activity of IDO and iNOS. This tolerance was abrogated in the presence of both IDO and iNOS inhibitors. A cross-regulatory pathway was observed between the IDO and NO pathways, in which the inhibition of IDO stimulated the iNOS pathway and vice versa.
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Affiliation(s)
- Qi-Xiang Ye
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China.,Department of Hematology and Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, P.R. China
| | - Lv-Hong Xu
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Pei-Jie Shi
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Ting Xia
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Jian-Pei Fang
- Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
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19
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Rossini AA, Parker DC, Phillips NE, Durie FH, Noelle RJ, Mordes JP, Greiner DL. Induction of Immunological Tolerance to Islet Allografts. Cell Transplant 2017; 5:49-52. [PMID: 8665076 DOI: 10.1177/096368979600500109] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
T-cell dependent activation of resting B cells involves the interaction of gp39 on T cells with its receptor, CD40, on B cells. We administered either a combination of T-cell-depleted splenic lymphocytes and anti-gp39 monoclonal antibody or antibody alone to establish islet allografts in mice without continuous immunosuppression. Fully allogeneic H-2q FVB islets were permanently accepted by chemically diabetic H-2b C57BL/6 mice provided that the recipients were pretreated with both T-cell-depleted donor spleen cells and anti-gp39 antibody. Antibody alone was less effective in prolonging allograft survival, but we did observe that anti-gp39 mAb alone can exert an independent, primary effect on islet allograft survival that was dose dependent. Targeting gp39, in combination with lymphocyte transfusion, might prove suitable for tolerance induction and allotransplantation without immunosuppression.
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Affiliation(s)
- A A Rossini
- Department of Medicine, University of Massachusetts Medical School, Worcester 01655, USA
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20
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Brady JL, Yamashita K, Lew AM. Enhanced Survival of Grafts Genetically Endowed with the Ability to Block CD2 and B7. Cell Transplant 2017. [DOI: 10.3727/000000001783986909] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Jamie L. Brady
- Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Parkville 3050, Australia
| | - Kenji Yamashita
- Kaneka Corporation, 1 – 8, Miyamae-Machi, Takasago-Cho, Takasago-Shi, Hyogo, 676, Japan
| | - Andrew M. Lew
- Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Parkville 3050, Australia
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21
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Kean LS, Turka LA, Blazar BR. Advances in targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy. Immunol Rev 2017; 276:192-212. [PMID: 28258702 PMCID: PMC5338458 DOI: 10.1111/imr.12523] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In the past decade, the power of harnessing T-cell co-signaling pathways has become increasingly understood to have significant clinical importance. In cancer immunotherapy, the field has concentrated on two related modalities: First, targeting cancer antigens through highly activated chimeric antigen T cells (CAR-Ts) and second, re-animating endogenous quiescent T cells through checkpoint blockade. In each of these strategies, the therapeutic goal is to re-ignite T-cell immunity, in order to eradicate tumors. In transplantation, there is also great interest in targeting T-cell co-signaling, but with the opposite goal: in this field, we seek the Yin to cancer immunotherapy's Yang, and focus on manipulating T-cell co-signaling to induce tolerance rather than activation. In this review, we discuss the major T-cell signaling pathways that are being investigated for tolerance induction, detailing preclinical studies and the path to the clinic for many of these molecules. These include blockade of co-stimulation pathways and agonism of coinhibitory pathways, in order to achieve the delicate state of balance that is transplant tolerance: a state which guarantees lifelong transplant acceptance without ongoing immunosuppression, and with preservation of protective immune responses. In the context of the clinical translation of immune tolerance strategies, we discuss the significant challenge that is embodied by the fact that targeted pathway modulators may have opposing effects on tolerance based on their impact on effector vs regulatory T-cell biology. Achieving this delicate balance holds the key to the major challenge of transplantation: lifelong control of alloreactivity while maintaining an otherwise intact immune system.
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Affiliation(s)
- Leslie S Kean
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA
- The Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Laurence A Turka
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Immune Tolerance Network, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
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22
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Esensten JH, Helou YA, Chopra G, Weiss A, Bluestone JA. CD28 Costimulation: From Mechanism to Therapy. Immunity 2016; 44:973-88. [PMID: 27192564 PMCID: PMC4932896 DOI: 10.1016/j.immuni.2016.04.020] [Citation(s) in RCA: 627] [Impact Index Per Article: 69.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Indexed: 02/07/2023]
Abstract
Ligation of the CD28 receptor on T cells provides a critical second signal alongside T cell receptor (TCR) ligation for naive T cell activation. Here, we discuss the expression, structure, and biochemistry of CD28 and its ligands. CD28 signals play a key role in many T cell processes, including cytoskeletal remodeling, production of cytokines, survival, and differentiation. CD28 ligation leads to unique epigenetic, transcriptional, and post-translational changes in T cells that cannot be recapitulated by TCR ligation alone. We discuss the function of CD28 and its ligands in both effector and regulatory T cells. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis. We outline the roles that CD28 and its family members play in human disease and we review the clinical efficacy of drugs that block CD28 ligands. Despite the centrality of CD28 and its family members and ligands to immune function, many aspects of CD28 biology remain unclear. Translation of a basic understanding of CD28 function into immunomodulatory therapeutics has been uneven, with both successes and failures. Such real-world results might stem from multiple factors, including complex receptor-ligand interactions among CD28 family members, differences between the mouse and human CD28 families, and cell-type specific roles of CD28 family members.
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Affiliation(s)
- Jonathan H Esensten
- Department of Laboratory Medicine, University of California, San Francisco, CA 94143, USA.
| | - Ynes A Helou
- Division of Rheumatology, Department of Medicine, Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, CA 94143, USA
| | - Gaurav Chopra
- Department of Chemistry, Purdue Center for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
| | - Arthur Weiss
- Division of Rheumatology, Department of Medicine, Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA
| | - Jeffrey A Bluestone
- Diabetes Center and Department of Medicine, University of California, San Francisco, CA 94143, USA.
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23
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Abstract
The ultimate outcome of alloreactivity versus tolerance following transplantation is potently influenced by the constellation of cosignaling molecules expressed by immune cells during priming with alloantigen, and the net sum of costimulatory and coinhibitory signals transmitted via ligation of these molecules. Intense investigation over the last two decades has yielded a detailed understanding of the kinetics, cellular distribution, and intracellular signaling networks of cosignaling molecules such as the CD28, TNF, and TIM families of receptors in alloimmunity. More recent work has better defined the cellular and molecular mechanisms by which engagement of cosignaling networks serve to either dampen or augment alloimmunity. These findings will likely aid in the rational development of novel immunomodulatory strategies to prolong graft survival and improve outcomes following transplantation.
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Affiliation(s)
- Mandy L Ford
- Emory Transplant Center and Department of Surgery, Emory University, Atlanta, GA 30322, USA.
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24
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Abstract
Generation of an effective immune response against foreign antigens requires two distinct molecular signals: a primary signal provided by the binding of antigen-specific T-cell receptor to peptide-MHC on antigen-presenting cells and a secondary signal delivered via the engagement of costimulatory molecules. Among various costimulatory signaling pathways, the interactions between CD40 and its ligand CD154 have been extensively investigated given their essential roles in the modulation of adaptive immunity. Here, we review current understanding of the role CD40/CD154 costimulation pathway has in alloimmunity, and summarize recent mechanistic and preclinical advances in the evaluation of candidate therapeutic approaches to target this receptor-ligand pair in transplantation.
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Affiliation(s)
- Tianshu Zhang
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Richard N Pierson
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
- Baltimore VA Medical Center, Baltimore, MD, USA
| | - Agnes M Azimzadeh
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
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25
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Louveau A, Nerrière-Daguin V, Vanhove B, Naveilhan P, Neunlist M, Nicot A, Boudin H. Targeting the CD80/CD86 costimulatory pathway with CTLA4-Ig directs microglia toward a repair phenotype and promotes axonal outgrowth. Glia 2015. [PMID: 26212105 DOI: 10.1002/glia.22894] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Among the costimulatory factors widely studied in the immune system is the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA4)-CD80/CD86 pathway, which critically controls the nature and duration of the T-cell response. In the brain, up-regulated expression of CD80/CD86 during inflammation has consistently been reported in microglia. However, the role of CD80/CD86 molecules has mainly been studied in a context of microglia-T cell interactions in pathological conditions, while the function of CD80/CD86 in the regulation of intrinsic brain cells remains largely unknown. In this study, we used a transgenic pig line in which neurons express releasable CTLA4-Ig, a synthetic molecule mimicking CTLA4 and binding to CD80/CD86. The effects of CTLA4-Ig on brain cells were analyzed after intracerebral transplantation of CTLA4-Ig-expressing neurons or wild-type neurons as control. This model provided in vivo evidence that CTLA4-Ig stimulated axonal outgrowth, in correlation with a shift of the nearby microglia from a compact to a ramified morphology. In a culture system, we found that the CTLA4-Ig-induced morphological change of microglia was mediated through CD86, but not CD80. This was accompanied by microglial up-regulated expression of the anti-inflammatory molecule Arginase 1 and the neurotrophic factor BDNF, in an astrocyte-dependent manner through the purinergic P2Y1 receptor pathway. Our study identifies for the first time CD86 as a key player in the modulation of microglia phenotype and suggests that CTLA4-Ig-derived compounds might represent new tools to manipulate CNS microglia.
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Affiliation(s)
- Antoine Louveau
- INSERM UMR 1064, ITUN, CHU Nantes, University of Nantes, France
| | | | - Bernard Vanhove
- INSERM UMR 1064, ITUN, CHU Nantes, University of Nantes, France
| | - Philippe Naveilhan
- INSERM UMR 1064, ITUN, CHU Nantes, University of Nantes, France.,INSERM UMR 913, IMAD, University of Nantes, France
| | | | - Arnaud Nicot
- INSERM UMR 1064, ITUN, CHU Nantes, University of Nantes, France
| | - Hélène Boudin
- INSERM UMR 1064, ITUN, CHU Nantes, University of Nantes, France.,INSERM UMR 913, IMAD, University of Nantes, France
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26
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Ciurea SO, Bayraktar UD. "No donor"? Consider a haploidentical transplant. Blood Rev 2015; 29:63-70. [PMID: 25307958 PMCID: PMC4379127 DOI: 10.1016/j.blre.2014.09.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 09/13/2014] [Accepted: 09/16/2014] [Indexed: 12/25/2022]
Abstract
Haploidentical stem cell transplantation (HaploSCT) is an attractive option for patients requiring a hematopoietic stem cell transplant who do not have an HLA-matched donor, because it is cheaper, can be performed faster, and may extend transplantation to virtually all patients in need. Significant advances have been made in the recent decade with dramatic improvement in treatment outcomes. Historically, overcoming the HLA-incompatibility barrier has been a significant limitation to the expansion of this form of transplant. While ex vivo T-cell depletion effectively prevented the development of acute GVHD, it was associated with a higher treatment-related mortality, in excess of 40% in some series, due to a significant delay in recovery of the adaptive immune system. Newer methods have successfully maintained the memory T cells in the graft and/or selectively depleted alloreactive T cells, and are associated with improved treatment outcomes. Post-transplant cyclophosphamide for GVHD prevention has proven very effective in controlling GVHD with lower incidence of infectious complications and treatment-related mortality-as low as 7% at 1 year-and has become the new standard in how this transplant is performed. Here, we reviewed the current experience with this approach and various other strategies employed to control alloreactivity in this setting, including selective depletion of T cells from the graft, as well as we discuss post-transplantation therapy to prevent disease relapse and improve immunologic reconstitution.
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Affiliation(s)
- Stefan O Ciurea
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Ulas D Bayraktar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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27
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Chong AS, Alegre ML. Transplantation tolerance and its outcome during infections and inflammation. Immunol Rev 2015; 258:80-101. [PMID: 24517427 DOI: 10.1111/imr.12147] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Much progress has been made toward understanding the mechanistic basis of transplantation tolerance in experimental models, which implicates clonal deletion of alloreactive T and B cells, induction of cell-intrinsic hyporesponsiveness, and dominant regulatory cells mediating infectious tolerance and linked suppression. Despite encouraging success in the laboratory, achieving tolerance in the clinic remains challenging, although the basis for these challenges is beginning to be understood. Heterologous memory alloreactive T cells generated by infections prior to transplantation have been shown to be a critical barrier to tolerance induction. Furthermore, infections at the time of transplantation and tolerance induction provide a pro-inflammatory milieu that alters the stability and function of regulatory T cells as well as the activation requirements and differentiation of effector T cells. Thus, infections can result in enhanced alloreactivity, resistance to tolerance induction, and destabilization of the established tolerance state. We speculate that these experimental findings have relevance to the clinic, where infections have been associated with allograft rejection and may be a causal event precipitating the loss of grafts after long periods of stable operational tolerance. Understanding the mechanisms by which infections prevent and destabilize tolerance can lead to therapies that promote stable life-long tolerance in transplant recipients.
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Affiliation(s)
- Anita S Chong
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL, USA
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28
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Sönmez E, Siemionow MZ. Nerve Allograft Transplantation. Plast Reconstr Surg 2015. [DOI: 10.1007/978-1-4471-6335-0_68] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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29
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Yamada Y, Ochiai T, Boskovic S, Nadazdin O, Oura T, Schoenfeld D, Cappetta K, Smith RN, Colvin RB, Madsen JC, Sachs DH, Benichou G, Cosimi AB, Kawai T. Use of CTLA4Ig for induction of mixed chimerism and renal allograft tolerance in nonhuman primates. Am J Transplant 2014; 14:2704-12. [PMID: 25394378 PMCID: PMC4236265 DOI: 10.1111/ajt.12936] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 06/18/2014] [Accepted: 07/12/2014] [Indexed: 01/25/2023]
Abstract
We have previously reported successful induction of renal allograft tolerance via a mixed chimerism approach in nonhuman primates. In those studies, we found that costimulatory blockade with anti-CD154 mAb was an effective adjunctive therapy for induction of renal allograft tolerance. However, since anti-CD154 mAb is not clinically available, we have evaluated CTLA4Ig as an alternative agent for effecting costimulation blockade in this treatment protocol. Two CTLA4Igs, abatacept and belatacept, were substituted for anti-CD154 mAb in the conditioning regimen (low dose total body irradiation, thymic irradiation, anti-thymocyte globulin and a 1-month posttransplant course of cyclosporine [CyA]). Three recipients treated with the abatacept regimen failed to develop comparable lymphoid chimerism to that achieved with anti-CD154 mAb treatment and these recipients rejected their kidney allografts early. With the belatacept regimen, four of five recipients developed chimerism and three of these achieved long-term renal allograft survival (>861, >796 and >378 days) without maintenance immunosuppression. Neither chimerism nor long-term allograft survival were achieved in two recipients treated with the belatacept regimen but with a lower, subtherapeutic dose of CyA. This study indicates that CD28/B7 blockade with belatacept can provide a clinically applicable alternative to anti-CD154 mAb for promoting chimerism and renal allograft tolerance.
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Affiliation(s)
- Yohei Yamada
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Takanori Ochiai
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Svjetlan Boskovic
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Ognjenka Nadazdin
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Tetsu Oura
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - David Schoenfeld
- Department of Biostatistics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Kate Cappetta
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Rex-Neal Smith
- Department of pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Robert B Colvin
- Department of pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Joren C. Madsen
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - David H. Sachs
- Transplant Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Gilles Benichou
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - A. Benedict Cosimi
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Tatsuo Kawai
- Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
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30
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Gracon ASA, Wilkes DS. Lung transplantation: chronic allograft dysfunction and establishing immune tolerance. Hum Immunol 2014; 75:887-94. [PMID: 24979671 PMCID: PMC4357397 DOI: 10.1016/j.humimm.2014.06.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 06/19/2014] [Accepted: 06/19/2014] [Indexed: 10/25/2022]
Abstract
Despite significant medical advances since the advent of lung transplantation, improvements in long-term survival have been largely unrealized. Chronic lung allograft dysfunction, in particular obliterative bronchiolitis, is the primary limiting factor. The predominant etiology of obliterative bronchiolitis involves the recipient's innate and adaptive immune response to the transplanted allograft. Current therapeutic strategies have failed to provide a definitive treatment paradigm to improve long-term outcomes. Inducing immune tolerance is an emerging therapeutic strategy that abrogates allograft rejection, avoids immunosuppression, and improves long-term graft function. The aim of this review is to discuss the key immunologic components of obliterative bronchiolitis, describe the state of establishing immune tolerance in transplantation, and highlight those strategies being evaluated in lung transplantation.
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Affiliation(s)
- Adam S A Gracon
- Department of Surgery and Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - David S Wilkes
- Departments of Medicine, Microbiology and Immunology, Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN, USA.
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31
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Esposito L, Hunter KMD, Clark J, Rainbow DB, Stevens H, Denesha J, Duley S, Dawson S, Coleman G, Nutland S, Bell GL, Moran C, Pekalski M, Todd JA, Wicker LS. Investigation of soluble and transmembrane CTLA-4 isoforms in serum and microvesicles. THE JOURNAL OF IMMUNOLOGY 2014; 193:889-900. [PMID: 24928993 PMCID: PMC4082723 DOI: 10.4049/jimmunol.1303389] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Expression of the CTLA-4 gene is absolutely required for immune homeostasis, but aspects of its molecular nature remain undefined. In particular, the characterization of the soluble CTLA-4 (sCTLA-4) protein isoform generated by an alternatively spliced mRNA of CTLA4 lacking transmembrane-encoding exon 3 has been hindered by the difficulty in distinguishing it from the transmembrane isoform of CTLA-4, Tm-CTLA-4. In the current study, sCTLA-4 has been analyzed using novel mAbs and polyclonal Abs specific for its unique C-terminal amino acid sequence. We demonstrate that the sCTLA-4 protein is secreted at low levels following the activation of primary human CD4+ T cells and is increased only rarely in the serum of autoimmune patients. Unexpectedly, during our studies aimed to define the kinetics of sCTLA-4 produced by activated human CD4+ T cells, we discovered that Tm-CTLA-4 is associated with microvesicles produced by the activated cells. The functional roles of sCTLA-4 and microvesicle-associated Tm-CTLA-4 warrant further investigation, especially as they relate to the multiple mechanisms of action described for the more commonly studied cell-associated Tm-CTLA-4.
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Affiliation(s)
- Laura Esposito
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Kara M D Hunter
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Jan Clark
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Daniel B Rainbow
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Helen Stevens
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Jennifer Denesha
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Simon Duley
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Sarah Dawson
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Gillian Coleman
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Sarah Nutland
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Gwynneth L Bell
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Carla Moran
- National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom
| | - Marcin Pekalski
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - John A Todd
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
| | - Linda S Wicker
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; and
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32
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Kirk AD, Guasch A, Xu H, Cheeseman J, Mead SI, Ghali A, Mehta AK, Wu D, Gebel H, Bray R, Horan J, Kean LS, Larsen CP, Pearson TC. Renal transplantation using belatacept without maintenance steroids or calcineurin inhibitors. Am J Transplant 2014; 14:1142-51. [PMID: 24684552 PMCID: PMC4642731 DOI: 10.1111/ajt.12712] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 01/27/2014] [Accepted: 02/12/2014] [Indexed: 01/25/2023]
Abstract
Kidney transplantation remains limited by toxicities of calcineurin inhibitors (CNIs) and steroids. Belatacept is a less toxic CNI alternative, but existing regimens rely on steroids and have higher rejection rates. Experimentally, donor bone marrow and sirolimus promote belatacept's efficacy. To investigate a belatacept-based regimen without CNIs or steroids, we transplanted recipients of live donor kidneys using alemtuzumab induction, monthly belatacept and daily sirolimus. Patients were randomized 1:1 to receive unfractionated donor bone marrow. After 1 year, patients were allowed to wean from sirolimus. Patients were followed clinically and with surveillance biopsies. Twenty patients were transplanted, all successfully. Mean creatinine (estimated GFR) was 1.10 ± 0.07 mg/dL (89 ± 3.56 mL/min) and 1.13 ± 0.07 mg/dL (and 88 ± 3.48 mL/min) at 12 and 36 months, respectively. Excellent results were achieved irrespective of bone marrow infusion. Ten patients elected oral immunosuppressant weaning, seven of whom were maintained rejection-free on monotherapy belatacept. Those failing to wean were successfully maintained on belatacept-based regimens supplemented by oral immunosuppression. Seven patients declined immunosuppressant weaning and three patients were denied weaning for associated medical conditions; all remained rejection-free. Belatacept and sirolimus effectively prevent kidney allograft rejection without CNIs or steroids when used following alemtuzumab induction. Selected, immunologically low-risk patients can be maintained solely on once monthly intravenous belatacept.
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Affiliation(s)
- A D Kirk
- Emory Transplant Center, Emory University, Atlanta, GA
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33
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Sugimoto K, Itoh T, Takita M, Shimoda M, Chujo D, SoRelle JA, Naziruddin B, Levy MF, Shimada M, Matsumoto S. Improving allogeneic islet transplantation by suppressing Th17 and enhancing Treg with histone deacetylase inhibitors. Transpl Int 2014; 27:408-15. [PMID: 24410777 DOI: 10.1111/tri.12265] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Revised: 07/01/2013] [Accepted: 01/07/2014] [Indexed: 12/23/2022]
Abstract
Islet transplantation is a new treatment for achieving insulin independence for patients with severe diabetes. However, major drawbacks of this treatment are the long graft survival, the necessity for immunosuppressive drugs, and the efficacy of transplantation. Donor-specific transfusion (DST) has been shown to reduce rejection after organ transplantation, potentially through enhanced regulatory T-cell (Treg) activity. However, recent findings have shown that activated Treg can be converted into Th17 cells. We focused on histone deacetylase inhibitors (HDACi) because it was reported that inhibition of HDAC activity prevented Treg differentiation into IL17-producing cells. We therefore sought to enhance Treg while suppressing Th17 cells using DST with HDACi to prolong graft survival. To stimulate Treg by DST, we used donor splenocytes. In DST with HDACi group, Foxp3 mRNA expression and Treg population increased in the thymus and spleen, whereas Th17 population decreased. qPCR analysis of lymphocyte mRNA indicated that Foxp3, IL-10, and TGF-b expression increased. However, interleukin 17a, Stat3 (Th17), and IFN-g expression decreased in DST + HDACi group, relative to DST alone. Moreover, DST treated with HDACi prolonged graft survival relative to controls in mice islet transplantation. DST with HDACi may therefore have utility in islet transplantation.
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Affiliation(s)
- Koji Sugimoto
- Baylor Research Institute Fort Worth Campus, Fort Worth, TX, USA; The Departments of Surgery, Tokushima University, Tokushima, Japan
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34
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Maltzman JS, Turka LA. T-cell costimulatory blockade in organ transplantation. Cold Spring Harb Perspect Med 2013; 3:a015537. [PMID: 24296352 DOI: 10.1101/cshperspect.a015537] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Before it became possible to derive T-cell lines and clones, initial experimentation on the activation requirements of T lymphocytes was performed on transformed cell lines, such as Jurkat. These studies, although technically correct, proved misleading as most transformed T cells can be activated by stimulation of the clonotypic T-cell receptor (TCR) alone. In contrast, once it became possible to study nontransformed T cells, it quickly became clear that TCR stimulation by itself is insufficient for optimal activation of naïve T cells, but in fact, induces a state of anergy. It then became clear that functional activation of T cells requires not only recognition of major histocompatibility complex (MHC) and peptide by the TCR, but also requires ligation of costimulatory receptors expressed on the cell surface.
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Affiliation(s)
- Jonathan S Maltzman
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104
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35
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Abstract
Seminal studies in rabbits and rodent transplantation models by Peter Medawar revealed that cellular processes, rather than humoral antibodies, are central to the acute rejection of transplanted organs, and much of basic transplantation research continues to be focused on the biology and control of these cells, which were subsequently shown to be T cells. However, the success of current immunosuppression at controlling T-cell-mediated rejection has resulted in an increasing awareness of antibody-mediated rejection in the clinic. This, in turn, has fueled an emerging interest in the biology of allospecific antibodies, the B cells that produce these antibodies, and the development of mouse models that allow their investigation. Here we summarize some of the more widely used mouse models that have been developed to study the immunobiology of alloreactivity, transplantation rejection and tolerance, and used to identify therapeutic strategies that modulate these events.
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Affiliation(s)
- Anita S Chong
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, Illinois 60637
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36
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Ikemoto T, Takita M, Levy MF, Shimada M, Naziruddin B. CD11b(+) cells in donor-specific transfusion prolonged allogenic skin graft survival through indoleamine 2,3-dioxygenase. Cell Immunol 2013; 283:81-90. [PMID: 23933136 DOI: 10.1016/j.cellimm.2013.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 06/12/2013] [Indexed: 11/17/2022]
Abstract
The aim of this study is to show the effect of donor-specific transfusion (DST) in inducing immunological tolerance mediated by regulatory T cells (Treg) and indoleamine 2,3-dioxygenase (IDO). Skin grafts from H2(d) Balb/c were transplanted into H2(k) C3H/He 7days after the infusion of donor splenocytes, isolated each immune cell populations. Graft survival prolonged in recipients who received splenocytes, MHC class II(+) CD90(-) cells and CD3(-)CD19(-) cells (p<0.001, p<0.05 and p<0.01, respectively). CD11b(+) cell infusion resulted in prolongation of graft survival when compared to CD11c(+) cell infusion (p<0.01). Foxp3(+)CD4(+)CD25(+) T cells were increased after the transplant in recipients infused with CD11b(+) cells (p<0.05). The mixed lymphocyte reaction showed donor-specificity (p<0.001). High IDO expression was observed in CD11b(+) cell infusion group. Graft survival with DST using IDO antagonist (1MT) were not prolonged. In conclusion, DST allows induction of donor-specific tolerance which involves Foxp3(+)CD4(+)CD25(+) T cells and IDO expression.
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Affiliation(s)
- Tetsuya Ikemoto
- Baylor Institute for Immunology Research, Baylor Research Institute, 3434 Live Oak, Dallas, TX 75204, USA.
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37
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Schroder PM, Khattar M, Deng R, Xie A, Chen W, Stepkowski SM. Transient combination therapy targeting the immune synapse abrogates T cell responses and prolongs allograft survival in mice. PLoS One 2013; 8:e69397. [PMID: 23894468 PMCID: PMC3722282 DOI: 10.1371/journal.pone.0069397] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 06/09/2013] [Indexed: 12/28/2022] Open
Abstract
T cells play a major role in allograft rejection, which occurs after T cell activation by the engagement of several functional molecules to form an immune synapse with alloantigen presenting cells. In this study, the immune synapse was targeted using mAbs directed to the TCR beta-chain (TCRβ) and lymphocyte function-associated antigen−1 (LFA1) to induce long-term allograft survival. Evaluation of antigen-specific T cell responses was performed by adoptively transferring CFSE labeled transgenic OT-II cells into wild-type mice and providing OVA peptide by intravenous injection. Graft survival studies were performed in mice by transplanting BALB/c ear skins onto the flanks of C57BL/6 recipients. The anti-TCRβ plus anti-LFA1 mAb combination (but not either mAb alone) abrogated antigen-specific T cell responses invitro and invivo. Transient combination therapy with these agents resulted in significantly prolonged skin allograft survival in mice (51±10 days; p<0.01) when compared to treatment with either anti-TCRβ mAb (24±5 days) or anti-LFA1 mAb (19±3 days) alone or no treatment (10±1 days). When lymphoid tissues from these mice were analyzed at different times post-transplant, only those receiving the combination of anti-TCRβ and anti-LFA1 mAbs demonstrated long-lasting reductions in total T cell numbers, cellular and humoral anti-donor responses, and expression of CD3 on the surface of T cells. These results demonstrate that transient anti-TCRβ and anti-LFA1 mAb combination therapy abrogates antigen-reactive T cell responses with long-lasting effects that significantly prolong allograft survival.
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Affiliation(s)
- Paul M. Schroder
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio, United States of America
| | - Mithun Khattar
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio, United States of America
| | - Ronghai Deng
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio, United States of America
- Organ Transplantation Center, 1 Affiliated Hospital, Sun-Yat Sen University, Guangzhou, China
| | - Aini Xie
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Cardiovascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Wenhao Chen
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio, United States of America
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- * E-mail: (WC); (SMS)
| | - Stanislaw M. Stepkowski
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio, United States of America
- * E-mail: (WC); (SMS)
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38
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Menon MC, Murphy B. Maintenance immunosuppression in renal transplantation. Curr Opin Pharmacol 2013; 13:662-71. [PMID: 23731524 DOI: 10.1016/j.coph.2013.05.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 05/03/2013] [Indexed: 12/28/2022]
Abstract
The need to maintain allograft recipients on immunosuppression is nearly universal. Immunosuppressive agents used in organ transplantation target one or more steps of the host alloimmune response, specifically processes related to CD4-positive T lymphocytes. Calcineurin-inhibitor based steroid-containing regimens have been the mainstay of maintenance immunosuppression over the last two decades. Newer agents have shown efficacy in this role in recent trials with comparable allograft and patient outcomes. These agents have permitted calcineurin-inhibitor minimization and steroid-sparing strategies in selected groups of patients.
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Affiliation(s)
- Madhav C Menon
- Ichan School of Medicine at Mount Sinai, New York, United States
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Modulating T-cell costimulation as new immunosuppressive concept in organ transplantation. Curr Opin Organ Transplant 2013; 17:368-75. [PMID: 22790071 DOI: 10.1097/mot.0b013e328355fc94] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE OF REVIEW Blockade of costimulatory signalling is a promising approach to inhibit T-cell responses and consequently allograft rejection. The last decade was marked by progress in understanding the details of various costimulatory pathways and by the development of biologicals targeting these pathways with the aim of selectively and efficiently modulating T-cell responses. RECENT FINDINGS Here we focus on the clinically relevant costimulatory pathways CD28:CD80/86, CD40:CD154 (CD40L), CD2:LFA-3 and ICAM:LFA-1. We will give a short overview of the physiologic function of these pathways and discuss results from preclinical and clinical studies of costimulation blockers targeting these pathways. SUMMARY The development of costimulation blockers for clinical application in the field of organ transplantation was delayed by several setbacks. However, belatacept has recently been approved as first in class for renal transplantation. Several additional costimulation blockers are under development with some having already entered into clinical trials. Costimulation blockers are a new class of rationally designed immunosuppressive drugs with considerable potential for improving outcome of organ transplantation.
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40
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Christensen AD, Skov S, Haase C. Local and systemic effects of co-stimulatory blockade using cytotoxic T lymphocyte antigen-4-immunoglobulin in dinitrofluorobenzene- and oxazolone-induced contact hypersensitivity in mice. Clin Exp Immunol 2013; 171:220-30. [PMID: 23286949 DOI: 10.1111/cei.12005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2012] [Indexed: 12/12/2022] Open
Abstract
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)-immunoglobulin (Ig) has immunosuppressive properties both in vivo and in vitro, but much is still unknown about the mechanisms by which CTLA-4-Ig exerts its immunosuppressive activities in vivo. The aim of this study was to investigate the effect of CTLA-4-Ig in a mouse model of contact hypersensitivity (CHS). The inflammatory response in the presence or absence of CTLA-4-Ig was evaluated by measuring the increase in ear thickness in sensitized animals after challenge. We observed a dose-dependent suppression of the ear swelling in both dinitrofluorobenzene (DNFB)- and oxazolone-induced CHS. The suppressive effect was still present 3 weeks after administration, even in the absence of circulating levels of CTLA-4-Ig. It was further shown that CTLA-4-Ig inhibits activation of T cells in the draining lymph node after sensitization and affects the maturation level of both dendritic cells and B cells. Furthermore, CTLA-4-Ig reduces infiltration of activated CD8(+) T cells into the inflamed ear tissue and suppresses both local and systemic inflammation, as illustrated by reduced expression of cytokines and chemokines in the inflamed ear and a reduced level of acute-phase proteins in circulation. Finally, our results suggest that CTLA-4-Ig has a mainly immunosuppressive effect during the sensitization phase. We conclude that CTLA-4-Ig induces long-term immunosuppression of both DNFB- and oxazolone-induced inflammation and our data are the first to compare the effect of this compound in both DNFB- and oxazolone-induced CHS and to show that CTLA-4-Ig exerts an immunosuppressive effect on both local and systemic inflammatory mediators which is mediated principally during the sensitization phase.
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Affiliation(s)
- A D Christensen
- Experimental Immunology Group, Department of Immunopharmacology, Novo Nordisk A/S, Måløv, Denmark
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41
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Lo DJ, Anderson DJ, Weaver TA, Leopardi F, Song M, Farris AB, Strobert EA, Jenkins J, Turgeon NA, Mehta AK, Larsen CP, Kirk AD. Belatacept and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion. Am J Transplant 2013; 13:320-8. [PMID: 23311611 PMCID: PMC3558532 DOI: 10.1111/j.1600-6143.2012.04342.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Revised: 10/02/2012] [Accepted: 10/15/2012] [Indexed: 01/25/2023]
Abstract
Belatacept is an inhibitor of CD28/B7 costimulation that is clinically indicated as a calcineurin inhibitor (CNI) alternative in combination with mycophenolate mofetil and steroids after renal transplantation. We sought to develop a clinically translatable, nonlymphocyte depleting, belatacept-based regimen that could obviate the need for both CNIs and steroids. Thus, based on murine data showing synergy between costimulation blockade and mTOR inhibition, we studied rhesus monkeys undergoing MHC-mismatched renal allotransplants treated with belatacept and the mTOR inhibitor, sirolimus. To extend prior work on costimulation blockade-resistant rejection, some animals also received CD2 blockade with alefacept (LFA3-Ig). Belatacept and sirolimus therapy successfully prevented rejection in all animals. Tolerance was not induced, as animals rejected after withdrawal of therapy. The regimen did not deplete T cells. Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen, despite causing an intended depletion of memory T cells, and caused a marked reduction in regulatory T cells. Furthermore, alefacept-treated animals had a significantly increased incidence of CMV reactivation, suggesting that this combination overly compromised protective immunity. These data support belatacept and sirolimus as a clinically translatable, nondepleting, CNI-free, steroid-sparing immunomodulatory regimen that promotes sustained rejection-free allograft survival after renal transplantation.
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Affiliation(s)
- D J Lo
- Emory Transplant Center, Emory University, Atlanta, GA
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42
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Bayraktar UD, de Lima M, Ciurea SO. Advances in haploidentical stem cell transplantation. Rev Bras Hematol Hemoter 2012; 33:237-41. [PMID: 23049302 PMCID: PMC3415745 DOI: 10.5581/1516-8484.20110060] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2011] [Accepted: 04/29/2011] [Indexed: 11/27/2022] Open
Abstract
Hematopoietic stem cell transplantation from haploidentical donors is an attractive method of transplantation due to the immediate donor availability, ease of stem cell procurement and the possibility to collect additional donor cells for cellular therapy, if needed. Historically, maintaining T-cells in the graft has been associated with very high rates of graft-versus-host disease, while T-cell depleted haploidentical transplantation has been limited by a higher incidence of graft rejection and delayed immune reconstitution post-transplant. Recent approaches attempt to maintain the T-cells in the graft while effectively preventing the development of graft-versus-host disease post-transplant. Selective depletion of alloreactive T-cells post-transplant using high-dose post-transplant cyclophosphamide is under investigation as a promising alternative in haploidentical transplantation. While engraftment has improved and graft-versus-host disease is controlled with this approach, future directions should focus on optimizing conditioning regimens and the prevention of disease relapse post-transplant.
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Affiliation(s)
- Ulas Darda Bayraktar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
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43
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Coinhibitory molecules in autoimmune diseases. Clin Dev Immunol 2012; 2012:269756. [PMID: 22997525 PMCID: PMC3446788 DOI: 10.1155/2012/269756] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Accepted: 08/21/2012] [Indexed: 12/30/2022]
Abstract
Coinhibitory molecules such as CTLA-4, PD-1 and BTLA negatively regulate immune responses. Multiple studies indicate that the deficiency or mutation of coinhibitory molecules leads to the development of autoimmune diseases in mice and humans, indicating that the negative signals from coinhibitory molecules are crucial for the prevention of autoimmunity. In some conditions, the administration of decoy coinhibitory receptors (e.g., CTLA-4 Ig) or mAb against coinhibitory molecules suppresses the responses of self-reactive T cells in autoimmune diseases. Therefore, modulation of coinhibitory signals seems to be an attractive approach to induce tolerance in autoimmune diseases in humans where the disease-inducing self-antigens are not known. Particularly, administration of CTLA-4 Ig has shown great promise in animal models of autoimmune diseases and has been gaining increasing attention in clinical investigation in several autoimmune diseases in humans.
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44
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Priyadharshini B, Greiner DL, Brehm MA. T-cell activation and transplantation tolerance. Transplant Rev (Orlando) 2012; 26:212-22. [PMID: 22074786 PMCID: PMC3294261 DOI: 10.1016/j.trre.2011.09.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Revised: 08/16/2011] [Accepted: 09/02/2011] [Indexed: 12/28/2022]
Abstract
Transplantation of allogeneic or "nonself" tissues stimulates a robust immune response leading to graft rejection, and therefore, most recipients of allogeneic organ transplants require the lifelong use of immune suppressive agents. Excellent outcomes notwithstanding, contemporary immunosuppressive medications are toxic, are often not taken by patients, and pose long-term risks of infection and malignancy. The ultimate goal in transplantation is to develop new treatments that will supplant the need for general immunosuppression. Here, we will describe the development and application of costimulation blockade to induce transplantation tolerance and discuss how the diverse array of signals that act on T cells will determine the balance between graft survival and rejection.
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Affiliation(s)
- Bhavana Priyadharshini
- Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Biotech 2, Worcester, MA 01605
| | - Dale L. Greiner
- Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Biotech 2, Worcester, MA 01605
| | - Michael A. Brehm
- Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Biotech 2, Worcester, MA 01605
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45
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CD28 family and chronic rejection: "to belatacept...And beyond!". J Transplant 2012; 2012:203780. [PMID: 22720132 PMCID: PMC3376773 DOI: 10.1155/2012/203780] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Revised: 03/19/2012] [Accepted: 03/26/2012] [Indexed: 12/15/2022] Open
Abstract
Kidneys are one of the most frequently transplanted human organs. Immunosuppressive agents may prevent or reverse most acute rejection episodes; however, the graft may still succumb to chronic rejection. The immunological response involved in the chronic rejection process depends on both innate and adaptive immune response. T lymphocytes have a pivotal role in chronic rejection in adaptive immune response. Meanwhile, we aim to present a general overview on the state-of-the-art knowledge of the strategies used for manipulating the lymphocyte activation mechanisms involved in allografts, with emphasis on T-lymphocyte costimulatory and coinhibitory molecules of the B7-CD28 superfamily. A deeper understanding of the structure and function of these molecules improves both the knowledge of the immune system itself and their potential action as rejection inducers or tolerance promoters. In this context, the central role played by CD28 family, especially the relationship between CD28 and CTLA-4, becomes an interesting target for the development of immune-based therapies aiming to increase the survival rate of allografts and to decrease autoimmune phenomena. Good results obtained by the recent development of abatacept and belatacept with potential clinical use aroused better expectations concerning the outcome of transplanted patients.
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46
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Zhang J, Miao Q, Yang Y, Xiao B, Liu B, Cao J, Hao XY, Wang SW, Guo SZ. Effect of combined OX40Ig and CTLA4Ig gene local transfer on allograft rejection and the underlying mechanisms. J Surg Res 2012; 178:949-58. [PMID: 22694937 DOI: 10.1016/j.jss.2012.05.034] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Revised: 04/26/2012] [Accepted: 05/09/2012] [Indexed: 11/19/2022]
Abstract
BACKGROUND OX40Ig and CTLA4Ig fusion proteins have been suggested to induce immune tolerance and prevent rejection in allografts. The present study aims to investigate and compare the effects of ex vivo combined OX40Ig and CTLA4Ig lentivirus-mediated gene transfer on the long-term survival of the graft, as well as potential underlying mechanisms. METHODS We ex vivo transferred Brown Norway rats' superficial groin free flap with lentivirus vectors expressing OX40Ig or CTLA4Ig, or OX40Ig and CTLA4Ig combined, and transplanted the free flaps to Lewis rats. Short-course rapamycin was administered after transfection and transplantation. RT-PCR and Western blot were employed to evaluate expression of OX40Ig and CTLA4Ig. We assessed the survival time of the grafts and the degree of acute graft rejection after indicated treatment. Mixed lymphocyte reaction, flow cytometry, and ELISA were also used to evaluate systemic immune reactions. RESULTS Ex vivo transfer of OX40Ig or CTLA4Ig lentivirus vectors led to local expression of corresponding mRNA and proteins in the donor flap without affecting other organs of the recipient. The graft survival time was significantly expanded and rejection was markedly attenuated after transfection. Mixed lymphocyte reaction, flow cytometry (CD4(+) and CD8(+) T lymphocyte proportions), and serum ELISA analysis (IL-2, IFN-γ, IL-4, and IL-10) also showed decreased immune response following transfection. Combined OX40Ig and CTLA4Ig transfer exerted superior effect on improving graft survival and preventing graft rejection, inhibiting the immune response and decreasing the production of proinflammatory cytokines, compared with singular transfer of either OX40Ig or CTLA4Ig. CONCLUSION Combined ex vivo transfer of OX40Ig and CTLA4Ig lentivirus vectors provided superior benefits on long-term survival and restoration of the graft through inhibiting immune response and decreasing the production of proinflammatory cytokines.
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Affiliation(s)
- Jin Zhang
- Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China
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47
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McGrath MM, Najafian N. The role of coinhibitory signaling pathways in transplantation and tolerance. Front Immunol 2012; 3:47. [PMID: 22566929 PMCID: PMC3342378 DOI: 10.3389/fimmu.2012.00047] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Accepted: 02/28/2012] [Indexed: 12/25/2022] Open
Abstract
Negative costimulatory molecules, acting through so-called inhibitory pathways, play a crucial role in the control of T cell responses. This negative “second signal” opposes T cell receptor activation and leads to downregulation of T cell proliferation and promotes antigen specific tolerance. Much interest has focused upon these pathways in recent years as a method to control detrimental alloresponses and promote allograft tolerance. However, recent experimental data highlights the complexity of negative costimulatory pathways in alloimmunity. Varying effects are observed from molecules expressed on donor and recipient tissues and also depending upon the activation status of immune cells involved. There appears to be significant overlap and redundancy within these systems, rendering this a challenging area to understand and exploit therapeutically. In this article, we will review the literature at the current time regarding the major negative costimulation pathways including CTLA-4:B7, PD-1:PD-L1/PD-L2 and PD-L1:B7-1, B7-H3, B7-H4, HVEM:BTLA/CD160, and TIM-3:Galectin-9. We aim to outline the role of these pathways in alloimmunity and discuss their potential applications for tolerance induction in transplantation.
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Affiliation(s)
- Martina M McGrath
- Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital, Harvard Medical School Boston, MA, USA
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48
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Bayraktar UD, Champlin RE, Ciurea SO. Progress in haploidentical stem cell transplantation. Biol Blood Marrow Transplant 2012; 18:372-80. [PMID: 21835146 PMCID: PMC7209908 DOI: 10.1016/j.bbmt.2011.08.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Accepted: 08/01/2011] [Indexed: 11/27/2022]
Abstract
Haploidentical stem cell transplantation is an attractive form of transplantation because of the immediate donor availability, ease of stem cell procurement, and the possibility to further collect donor cells for cellular therapy. Historically, maintaining T cells in the graft has been associated with very high rates of graft-versus-host-disease (GVHD), whereas T cell-depleted haploidentical transplantation has been limited by a higher incidence of graft rejection and nonrelapse mortality related to infectious complications as a result of delayed immune reconstitution posttransplantation. Recent approaches have attempted to eliminate the alloreactive T cells to prevent GVHD posttransplantation. Administration of high-dose cyclophosphamide early posttransplantation in combination with tacrolimus and mycophenolate mofetil has produced engraftment and GVHD rates similar to HLA-matched sibling transplants, suggesting that the most important barriers against successful haploidentical transplantation can be overcome. Future directions should focus on optimizing conditioning regimens for different diseases and prevention of disease relapse posttransplantation.
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Affiliation(s)
- Ulas D Bayraktar
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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49
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Koshika T, Phelps C, Fang J, Lee SE, Fujita M, Ayares D, Cooper DKC, Hara H. Relative efficiency of porcine and human cytotoxic T-lymphocyte antigen 4 immunoglobulin in inhibiting human CD4+ T-cell responses co-stimulated by porcine and human B7 molecules. Immunology 2012; 134:386-97. [PMID: 22043861 DOI: 10.1111/j.1365-2567.2011.03496.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
α1,3-Galactosyltransferase gene-knockout pigs transgenic for porcine cytotoxic T-lymphocyte antigen 4 immunoglobulin (pCTLA4-Ig) have been produced to reduce T-cell-mediated rejection following xenotransplantation. The level of soluble pCTLA4-Ig in their blood was greatly in excess of the therapeutic level in patients, rendering the pigs immune-incompetent. Soluble pCTLA4-Ig produced by these transgenic pigs was evaluated for binding to porcine and human (h) B7 molecules, and for its inhibitory effect on allogeneic and xenogeneic human T-cell responses. Porcine CTLA4-Ig-expressing peripheral blood mononuclear cells (PBMCs) and aortic endothelial cells (AECs) were evaluated for their direct inhibitory effect on hCD4+ T-cell responses. Soluble pCTLA4-Ig and purified hCTLA4-Ig showed similar binding to pB7 molecules, but pCTLA4-Ig showed significantly less binding to hB7 molecules. The pCTLA4-Ig and hCTLA4-Ig inhibited the response of hCD4+ T cells to pAECs equally, but pCTLA4-Ig was less successful in inhibiting the human allogeneic response. The hCD4+ T-cell response to PBMCs from pCTLA4-Ig pigs was significantly lower than that of non-pCTLA4-Ig pigs. Although pCTLA4-Ig was detected in the cytoplasm of pCTLA4-Ig-expressing pAECs, only a minimal level of soluble pCTLA4-Ig was detected in the supernatant during culture, and pCTLA4-Ig-expressing pAECs did not inhibit the xenogeneic direct human T-cell response. High-level tissue-specific production of pCTLA4-Ig may be required for sufficient immunosuppression for organ or cell (e.g., islets) transplantation.
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Affiliation(s)
- Tadatsura Koshika
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, PA, USA.
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50
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Kitchens WH, Haridas D, Wagener ME, Song M, Kirk AD, Larsen CP, Ford ML. Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8(+) memory T cells. Am J Transplant 2012; 12:69-80. [PMID: 21942986 PMCID: PMC3467016 DOI: 10.1111/j.1600-6143.2011.03762.x] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The success of belatacept in late-stage clinical trials inaugurates the arrival of a new class of immunosuppressants based on costimulatory blockade, an immunosuppression strategy that disrupts essential signals required for alloreactive T-cell activation. Despite having improved renal function, kidney transplant recipients treated with belatacept experienced increased rates of acute rejection. This finding has renewed focus on costimulatory blockade-resistant rejection and specifically the role of alloreactive memory T cells in mediating this resistance. To study the mechanisms of costimulatory blockade-resistant rejection and enhance the clinical efficacy of costimulatory blockade, we developed an experimental transplant system that models a donor-specific memory CD8(+) T-cell response. After confirming that graft-specific memory T cells mediate costimulatory blockade-resistant rejection, we characterized the role of integrins in this rejection. The resistance of memory T cells to costimulatory blockade was abrogated when costimulatory blockade was coupled with either anti-VLA-4 or anti-LFA-1. Mechanistic studies revealed that in the presence of costimulatory blockade, anti-VLA-4 impaired T-cell trafficking to the graft but not memory T-cell recall effector function, whereas anti-LFA-1 attenuated both trafficking and memory recall effector function. As antagonists against these integrins are clinically approved, these findings may have significant translational potential for future clinical transplant trials.
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Affiliation(s)
| | - D. Haridas
- Emory Transplant Center, Emory University, Atlanta, GA
| | - M. E. Wagener
- Emory Transplant Center, Emory University, Atlanta, GA
| | - M. Song
- Emory Transplant Center, Emory University, Atlanta, GA
| | - A. D. Kirk
- Emory Transplant Center, Emory University, Atlanta, GA
| | - C. P. Larsen
- Emory Transplant Center, Emory University, Atlanta, GA
| | - M. L. Ford
- Emory Transplant Center, Emory University, Atlanta, GA,Corresponding Author: Mandy L. Ford Mailing Address: 101 Woodruff Circle, WMRB 5105; Atlanta, GA 30322 Phone: 404-727-2900 Fax: 404-727-3660
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