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Iesari S, Nava FL, Zais IE, Coubeau L, Ferraresso M, Favi E, Lerut J. Advancing immunosuppression in liver transplantation: A narrative review. Hepatobiliary Pancreat Dis Int 2024; 23:441-448. [PMID: 38523030 DOI: 10.1016/j.hbpd.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 03/14/2024] [Indexed: 03/26/2024]
Abstract
Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation (LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solid-organ transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.
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Affiliation(s)
- Samuele Iesari
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Francesca Laura Nava
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Ilaria Elena Zais
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Laurent Coubeau
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium; Service de Chirurgie et Transplantation Abdominale, Cliniques Universitaires Saint-Luc, 55 Avenue Hippocrate, 1200 Brussels, Belgium
| | - Mariano Ferraresso
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 19 Via della Commenda, 20122 Milan, Italy
| | - Evaldo Favi
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 19 Via della Commenda, 20122 Milan, Italy.
| | - Jan Lerut
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium
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Siemionow M, Cwykiel J, Brodowska S, Chambily L. Human Multi-Chimeric Cell (HMCC) Therapy as a Novel Approach for Tolerance Induction in Transplantation. Stem Cell Rev Rep 2023; 19:2741-2755. [PMID: 37603137 PMCID: PMC10661767 DOI: 10.1007/s12015-023-10608-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2023] [Indexed: 08/22/2023]
Abstract
Cellular therapies are regarded as the most promising approach for inducing transplant tolerance without life-long immunosuppression in solid organ and vascularized composite allotransplantation (VCA). Currently, no therapies are achieving this goal. This study introduces a novel Human Multi-Chimeric Cell (HMCC) line created by fusion of umbilical cord blood (UCB) cells, from three unrelated donors as an alternative therapeutic approach to bone marrow transplantation and tolerance induction in solid organ and VCA transplants. We performed eighteen ex vivo polyethylene glycol mediated fusions of human UCB cells from three unrelated donors to create HMCC. Mononuclear cells labeled with PKH26, PKH67, and eFluor™ 670 fluorescent dyes were fused and sorted creating a new population of triple-labeled (PKH26/PKH67/eFluor™ 670) HMCC. The creation of HMCC from three unrelated human UCB donors was confirmed by flow cytometry and confocal microscopy. Genotyping analyses determined the tri-chimeric state of HMCC by presence of parent alleles and selected loci specific for each of three UCB donors. Phenotype characterization confirmed hematopoietic markers distribution, comparable to UCB donors. HMCC maintained viability and displayed a low apoptosis level. The COMET assay revealed absence of genotoxicity, confirming fusion safety. Colony forming units assay showed clonogenic properties of HMCC. This study confirmed the feasibility of HMCC creation from three unrelated human UCB donors and characterized tri-chimeric state, hematopoietic phenotype, viability, safety, and clonogenic properties of HMCC. The created HMCC line, representing genotype characteristics of three unrelated human UCB donors, introduces a novel therapeutic approach for bone marrow, solid organ, and VCA transplants.
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Affiliation(s)
- Maria Siemionow
- Department of Traumatology, Orthopaedics and Hand Surgery, Poznan University of Medical Sciences, Poznan, Poland.
- Department of Orthopaedics, University of Illinois at Chicago, 900 South Ashland Ave., Room# 3356, Molecular Biology Research Building, Chicago, IL, 60607, USA.
| | - Joanna Cwykiel
- Department of Orthopaedics, University of Illinois at Chicago, 900 South Ashland Ave., Room# 3356, Molecular Biology Research Building, Chicago, IL, 60607, USA
| | - Sonia Brodowska
- Department of Orthopaedics, University of Illinois at Chicago, 900 South Ashland Ave., Room# 3356, Molecular Biology Research Building, Chicago, IL, 60607, USA
| | - Lucile Chambily
- Department of Orthopaedics, University of Illinois at Chicago, 900 South Ashland Ave., Room# 3356, Molecular Biology Research Building, Chicago, IL, 60607, USA
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Vianna R, Gaynor JJ, Selvaggi G, Farag A, Garcia J, Tekin A, Tabbara MM, Ciancio G. Liver Inclusion Appears to Be Protective Against Graft Loss-Due-to Chronic But Not Acute Rejection Following Intestinal Transplantation. Transpl Int 2023; 36:11568. [PMID: 37779512 PMCID: PMC10538304 DOI: 10.3389/ti.2023.11568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/28/2023] [Indexed: 10/03/2023]
Abstract
In intestinal transplantation, while other centers have shown that liver-including allografts have significantly more favorable graft survival and graft loss-due-to chronic rejection (CHR) rates, our center has consistently shown that modified multivisceral (MMV) and full multivisceral (MV) allografts have significantly more favorable acute cellular rejection (ACR) and severe ACR rates compared with isolated intestine (I) and liver-intestine (LI) allografts. In the attempt to resolve this apparent discrepancy, we performed stepwise Cox multivariable analyses of the hazard rates of developing graft loss-due-to acute rejection (AR) vs. CHR among 350 consecutive intestinal transplants at our center with long-term follow-up (median: 13.5 years post-transplant). Observed percentages developing graft loss-due-to AR and CHR were 14.3% (50/350) and 6.6% (23/350), respectively. Only one baseline variable was selected into the Cox model indicating a significantly lower hazard rate of developing graft loss-due-to AR: Transplant Type MMV or MV (p < 0.000001). Conversely, two baseline variables were selected into the Cox model indicating a significantly lower hazard rate of developing graft loss-due-to CHR: Received Donor Liver (LI or MV) (p = 0.002) and Received Induction (p = 0.007). In summary, while MMV/MV transplants (who receive extensive native lymphoid tissue removal) offered protection against graft loss-due-to AR, liver-containing grafts appeared to offer protection against graft loss-due-to CHR, supporting the results of other studies.
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Affiliation(s)
- Rodrigo Vianna
- Department of Surgery, Miami Transplant Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Jeffrey J. Gaynor
- Department of Surgery, Miami Transplant Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Gennaro Selvaggi
- Department of Surgery, Miami Transplant Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Ahmed Farag
- Department of Surgery, Miami Transplant Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
- Department of Surgery, Zagazig University School of Medicine, Zagazig, Egypt
| | - Jennifer Garcia
- Department of Pediatrics, Miami Transplant Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Akin Tekin
- Department of Surgery, Miami Transplant Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Marina M. Tabbara
- Department of Surgery, Miami Transplant Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Gaetano Ciancio
- Department of Surgery, Miami Transplant Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
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Li XC. Robert S. Schwartz, MD, a transformative figure in immunosuppression that revolutionized transplantation. FRONTIERS IN TRANSPLANTATION 2023; 2:1258950. [PMID: 38993915 PMCID: PMC11235212 DOI: 10.3389/frtra.2023.1258950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 08/16/2023] [Indexed: 07/13/2024]
Abstract
While the transplant community celebrated more than a million transplant patients in the United States, we are reminded that our journey to such a celebratory success is the results of remarkable breakthroughs and brilliant innovators. Among those, immunosuppression drugs are undoubtedly a cornerstone of transplant success, an area where Dr. Robert Schwartz is undeniably a transformative figure and a pioneer. His seminal studies on 6-mercaptopurine in 1959 gave birth to an entirely new specialty of immunosuppression that dramatically accelerated the advancement of clinical organ transplantation.
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Affiliation(s)
- Xian C Li
- Immunobiology and Transplant Science Center and Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
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Steiner R, Pilat N. The potential for Treg-enhancing therapies in transplantation. Clin Exp Immunol 2023; 211:122-137. [PMID: 36562079 PMCID: PMC10019131 DOI: 10.1093/cei/uxac118] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 09/21/2022] [Accepted: 12/22/2022] [Indexed: 12/24/2022] Open
Abstract
Since the discovery of regulatory T cells (Tregs) as crucial regulators of immune tolerance against self-antigens, these cells have become a promising tool for the induction of donor-specific tolerance in transplantation medicine. The therapeutic potential of increasing in vivoTreg numbers for a favorable Treg to Teff cell ratio has already been demonstrated in several sophisticated pre-clinical models and clinical pilot trials. In addition to improving cell quantity, enhancing Treg function utilizing engineering techniques led to encouraging results in models of autoimmunity and transplantation. Here we aim to discuss the most promising approaches for Treg-enhancing therapies, starting with adoptive transfer approaches and ex vivoexpansion cultures (polyclonal vs. antigen specific), followed by selective in vivostimulation methods. Furthermore, we address next generation concepts for Treg function enhancement (CARs, TRUCKs, BARs) as well as the advantages and caveats inherit to each approach. Finally, this review will discuss the clinical experience with Treg therapy in ongoing and already published clinical trials; however, data on long-term results and efficacy are still very limited and many questions that might complicate clinical translation remain open. Here, we discuss the hurdles for clinical translation and elaborate on current Treg-based therapeutic options as well as their potencies for improving long-term graft survival in transplantation.
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Affiliation(s)
- Romy Steiner
- Department of General Surgery, Medical University of Vienna, Vienna, Austria
- Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
- Center for Biomedical Research, Medical University of Vienna, Vienna, Austria
| | - Nina Pilat
- Correspondence: Nina Pilat, PhD, Department of Cardiac Surgery, Center for Biomedical Research, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
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Pilat N, Sprent J. Treg Therapies Revisited: Tolerance Beyond Deletion. Front Immunol 2021; 11:622810. [PMID: 33633742 PMCID: PMC7902070 DOI: 10.3389/fimmu.2020.622810] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 12/14/2020] [Indexed: 02/02/2023] Open
Abstract
Induction of immune tolerance is the Holy Grail in transplantation medicine and autoimmunity. Currently, patients are required to use immunosuppressive drugs for the rest of their lives, resulting in unwanted side effects and complication from global suppression of the immune response. It is well established that regulatory T cells (Tregs) are critical for the maintenance of immune tolerance towards self-antigens by several mechanisms of immune regulation, in parallel with intrathymic deletion of self-reactive T cells during ontogeny. Therefore, approaches for increasing Treg numbers or function in vivo could provide an all-purpose solution for tolerance induction. Currently, most state-of-the-art therapeutics for treating autoimmune diseases or preventing allograft rejection work either by general immunosuppression or blocking inflammatory reactions and are non-specific. Hence, these approaches cannot provide satisfactory long-term results, let alone a cure. However, in animal models the therapeutic potential of Treg expansion for inducing effective tolerance has now been demonstrated in various models of autoimmunity and allogeneic transplantation. Here, we focus on therapies for increasing the size of the Treg pool by expanding endogenous Treg numbers in vivo or by adoptive transfer of Tregs. In particular, we discuss IL-2 based approaches (low dose IL-2, IL-2 complexes) for inducing Treg expansion in vivo as well as cell-based approaches (polyclonal, antigen specific, or cell engineered) for adoptive Treg therapy. We also mention new questions arising from the first clinical studies on Treg therapy in the fields of transplantation and autoimmunity.
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Affiliation(s)
- Nina Pilat
- Section of Transplantation Immunology, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Jonathan Sprent
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia,St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia,*Correspondence: Jonathan Sprent,
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Aysan E, Yucesan E, Goncu B, Idiz UO. Fresh Tissue Parathyroid Allotransplantation from a Cadaveric Donor without Immunosuppression: A 3-Year Follow-Up. Am Surg 2020. [DOI: 10.1177/000313482008600405] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Erhan Aysan
- Department of General Surgery Yeditepe University Faculty of Medicine Istanbul, Turkey
| | - Emrah Yucesan
- Institute of Life Sciences and Biotechnology Bezmialem Vakif University Istanbul, Turkey
| | - Beyza Goncu
- Experimental Research Center Bezmialem Vakif University Istanbul, Turkey
| | - Ufuk Oguz Idiz
- Department of Immunology DETAE Istanbul University Istanbul, Turkey
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Cao P, Sun Z, Feng C, Zhang J, Zhang F, Wang W, Zhao Y. Myeloid-derived suppressor cells in transplantation tolerance induction. Int Immunopharmacol 2020; 83:106421. [PMID: 32217462 DOI: 10.1016/j.intimp.2020.106421] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 02/29/2020] [Accepted: 03/16/2020] [Indexed: 02/06/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells derived from bone marrow. These cells are developed from immature myeloid cells and have strong negative immunomodulatory effects. In the context of pathology (such as tumor, autoimmune disease, trauma, and burns), MDSCs accumulate around tumor and inflammatory tissues, where their main role is to inhibit the function of effector T cells and promote the recruitment of regulatory T cells. MDSCs can be used in organ transplantation to regulate the immune responses that participate in rejection of the transplanted organ. This effect is achieved by increasing the production of MDSCs in vivo or transfusion of MDSCs induced in vitro to establish immune tolerance and prolong the survival of the graft. In this review, we discuss the efficacy of MDSCs in a variety of transplantation studies as well as the induction of immune tolerance to prevent transplant rejection through the use of common clinical immunosuppressants combined with MDSCs.
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Affiliation(s)
- Peng Cao
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Zejia Sun
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Chang Feng
- Transplantation Biology Research Division, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Jiandong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Feilong Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Wei Wang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
| | - Yong Zhao
- Transplantation Biology Research Division, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing 100101, China
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Costa G, Parekh N, Osman M, Armanyous S, Fujiki M, Abu-Elmagd K. Composite and Multivisceral Transplantation: Nomenclature, Surgical Techniques, Current Practice, and Long-term Outcome. Surg Clin North Am 2018; 99:129-151. [PMID: 30471738 DOI: 10.1016/j.suc.2018.09.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The successful development of multivisceral and composite visceral transplantation is among the milestones in the recent history of human organ transplantation. All types of gastrointestinal transplantation have evolved to be the standard of care for patients with gut failure and complex abdominal pathologic conditions. The outcome has markedly improved over the last 3 decades owing to technical innovation, novel immunosuppression, and better postoperative care. Recent data documented significant improvement in the long-term therapeutic indices of all types of visceral transplantation close to that achieved with thoracic and solid abdominal organs.
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Affiliation(s)
- Guilherme Costa
- Center for Gut Rehabilitation and Transplantation, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA
| | - Neha Parekh
- Center for Gut Rehabilitation and Transplantation, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA
| | - Mohammed Osman
- Center for Gut Rehabilitation and Transplantation, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA
| | - Sherif Armanyous
- Department of Nephrology, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA
| | - Masato Fujiki
- Center for Gut Rehabilitation and Transplantation, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA
| | - Kareem Abu-Elmagd
- Center for Gut Rehabilitation and Transplantation, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA; Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA.
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Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells of the myeloid lineage upregulated by mediators of inflammation, such as IL-2, granulocyte colony-stimulating factor, and S100A8/A9. These cells have been studied extensively by tumor biologists. Because of their robust immunosuppressive potential, MDSCs have stirred recent interest among transplant immunologists as well. MDSCs inhibit T-cell responses through, among other mechanisms, the activity of arginase-1 and inducible nitric oxide synthase, and the expansion of T regulatory cells. In the context of transplantation, MDSCs have been studied in several animal models, and to a lesser degree in humans. Here, we will review the immunosuppressive qualities of this important cell type and discuss the relevant studies of MDSCs in transplantation. It may be possible to exploit the immunosuppressive capacity of MDSCs for the benefit of transplant patients.
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Costa G, Parekh N, Osman M, Armanyous S, Fujiki M, Abu-Elmagd K. Composite and Multivisceral Transplantation: Nomenclature, Surgical Techniques, Current Practice, and Long-term Outcome. Gastroenterol Clin North Am 2018; 47:393-415. [PMID: 29735032 DOI: 10.1016/j.gtc.2018.01.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
The successful development of multivisceral and composite visceral transplantation is among the milestones in the recent history of human organ transplantation. All types of gastrointestinal transplantation have evolved to be the standard of care for patients with gut failure and complex abdominal pathologic conditions. The outcome has markedly improved over the last 3 decades owing to technical innovation, novel immunosuppression, and better postoperative care. Recent data documented significant improvement in the long-term therapeutic indices of all types of visceral transplantation close to that achieved with thoracic and solid abdominal organs.
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Affiliation(s)
- Guilherme Costa
- Center for Gut Rehabilitation and Transplantation, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA
| | - Neha Parekh
- Center for Gut Rehabilitation and Transplantation, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA
| | - Mohammed Osman
- Center for Gut Rehabilitation and Transplantation, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA
| | - Sherif Armanyous
- Department of Nephrology, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA
| | - Masato Fujiki
- Center for Gut Rehabilitation and Transplantation, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA
| | - Kareem Abu-Elmagd
- Center for Gut Rehabilitation and Transplantation, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA; Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk A100, Cleveland, OH 44195, USA.
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12
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Wu G, Cruz RJ. Liver-inclusive intestinal transplantation results in decreased alloimmune-mediated rejection but increased infection. Gastroenterol Rep (Oxf) 2017; 6:29-37. [PMID: 29479440 PMCID: PMC5806397 DOI: 10.1093/gastro/gox043] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Accepted: 11/21/2017] [Indexed: 12/15/2022] Open
Abstract
Background and aims A co-transplanted liver allograft has been thought to protect other organs from rejection-mediated injury; however, detailed analyses of co-transplanted liver on intestinal allograft outcomes have not been conducted to date. The aim of the study was to compare immune-mediated injury, causes of graft failure and clinical outcomes between recipients who underwent either a liver-inclusive intestinal transplant (LITx) or liver-exclusive intestinal transplant (LETx). Methods Between May 2000 and May 2010, 212 adult patients undergoing LITx (n =76) and LETx (n =136) were included. LITx underwent either liver combined intestinal or full multivisceral transplantation. LETx underwent either isolated intestinal or modified multivisceral transplantation. Results During 44.9 ± 31.4 months of follow-up, death-censored intestinal graft survival was significantly higher for LITx than LETx (96.9%, 93.2% and 89.9% vs 91.4%, 69.3% and 60.0% at 1, 3 and 5 years; p =0.0001). Incidence of graft loss due to rejection was higher in LETx than in LITx (30.9% vs 6.6%; p <0.0001), while infection was the leading cause of graft loss due to patient death in LITx (25.0% vs 5.1%; p <0.0001). Despite similar immunosuppression, the average number (0.87 vs 1.42, p =0.02) and severity of acute cellular rejection episode (severe grade: 7.9% vs 21.3%; p =0.01) were lower in LITx than in LETx. Incidence of acute antibody-mediated rejection was also significantly lower in LITx than in LETx (3.6% vs 15.2%; p =0.03). Incidence of chronic rejection was reduced in LITx (3.9% vs 24.3%; p =0.0002). Conclusions Intestinal allografts with a liver component appear to decrease risk of rejection but increase risk of infection. Our findings emphasize that LITx has characteristic immunologic and clinical features. Lower immunosuppression may need to be considered for patients who undergo LITx to attenuate increased risk of infection.
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Affiliation(s)
- Guosheng Wu
- Department of Gastrointestinal Surgery, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shannxi, China
| | - Ruy J Cruz
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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Massart A, Ghisdal L, Abramowicz M, Abramowicz D. Operational tolerance in kidney transplantation and associated biomarkers. Clin Exp Immunol 2017; 189:138-157. [PMID: 28449211 DOI: 10.1111/cei.12981] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2017] [Indexed: 12/30/2022] Open
Abstract
In the 1960s, our predecessors won a historical battle against acute rejection and ensured that transplantation became a common life-saving treatment. In parallel with this success, or perhaps because of it, we lost the battle for long-lived transplants, being overwhelmed with chronic immune insults and the toxicities of immunosuppression. It is likely that current powerful treatments block acute rejection, but at the same time condemn the few circulating donor cells that would have been able to elicit immunoregulatory host responses towards the allograft. Under these conditions, spontaneously tolerant kidney recipients - i.e. patients who maintain allograft function in the absence of immunosuppression - are merely accidents; they are scarce, mysterious and precious. Several teams pursue the goal of finding a biomarker that would guide us towards the 'just right' level of immunosuppression that avoids rejection while leaving some space for donor immune cells. Some cellular assays are attractive because they are antigen-specific, and provide a comprehensive view of immune responses toward the graft. These seem to closely follow patient regulatory capacities. However, these tests are cumbersome, and require abundant cellular material from both donor and recipient. The latest newcomers, non-antigen-specific recipient blood transcriptomic biomarkers, offer the promise that a practicable and simple signature may be found that overcomes the complexity of a system in which an infinite number of individual cell combinations can lead possibly to graft acceptance. Biomarker studies are as much an objective - identifying tolerant patients, enabling tolerance trials - as a means to deciphering the underlying mechanisms of one of the most important current issues in transplantation.
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Affiliation(s)
- A Massart
- Department of Nephrology, Dialysis, and Transplantation, CUB Hôpital Erasme and Institute of Interdisciplinary Research in Molecular and Human Biology (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium
| | - L Ghisdal
- Department of Nephrology, Centre Hospitalier EpiCURA, Baudour, Belgium
| | - M Abramowicz
- Department of Human Genetics, CUB Hôpital Erasme and Institute of Interdisciplinary Research in Molecular and Human Biology (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium
| | - D Abramowicz
- Department of Nephrology, Universitair Ziekenhuis Antwerpen and Antwerp University, Antwerp, Belgium
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14
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Mohr Gregoriussen AM, Bohr HG. A Novel Model on DST-Induced Transplantation Tolerance by the Transfer of Self-Specific Donor tTregs to a Haplotype-Matched Organ Recipient. Front Immunol 2017; 8:9. [PMID: 28270810 PMCID: PMC5319400 DOI: 10.3389/fimmu.2017.00009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 01/04/2017] [Indexed: 12/27/2022] Open
Abstract
Donor-specific blood transfusion (DST) can lead to significant prolongation of allograft survival in experimental animal models and sometimes human recipients of solid organs. The mechanisms responsible for the beneficial effect on graft survival have been a topic of research and debate for decades and are not yet fully elucidated. Once we discover how the details of the mechanisms involved are linked, we could be within reach of a procedure making it possible to establish donor-specific tolerance with minimal or no immunosuppressive medication. Today, it is well established that CD4+Foxp3+ regulatory T cells (Tregs) are indispensable for maintaining immunological self-tolerance. A large number of animal studies have also shown that Tregs are essential for establishing and maintaining transplantation tolerance. In this paper, we present a hypothesis of one H2-haplotype-matched DST-induced transplantation tolerance (in mice). The formulated hypothesis is based on a re-interpretation of data from an immunogenetic experiment published by Niimi and colleagues in 2000. It is of importance that the naïve recipient mice in this study were never immunosuppressed and were therefore fully immune competent during the course of tolerance induction. Based on the immunological status of the recipients, we suggest that one H2-haplotype-matched self-specific Tregs derived from the transfusion blood can be activated and multiply in the host by binding to antigen-presenting cells presenting allopeptides in their major histocompatibility complex (MHC) class II (MHC-II). We also suggest that the endothelial and epithelial cells within the solid organ allograft upregulate the expression of MHC-II and attract the expanded Treg population to suppress inflammation within the graft. We further suggest that this biological process, here termed MHC-II recruitment, is a vital survival mechanism for organs (or the organism in general) when attacked by an immune system.
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Affiliation(s)
| | - Henrik Georg Bohr
- Department of Chemistry, The Technical University of Denmark , Lyngby , Denmark
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Emond JC, Griesemer AD. Tolerance in clinical liver transplantation: The long road ahead. Hepatology 2017; 65:411-413. [PMID: 27718261 DOI: 10.1002/hep.28862] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 09/27/2016] [Accepted: 09/29/2016] [Indexed: 12/15/2022]
Affiliation(s)
- Jean C Emond
- Department of Surgery, Columbia University, New York, NY
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16
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Bharadwaj S, Tandon P, Gohel TD, Brown J, Steiger E, Kirby DF, Khanna A, Abu-Elmagd K. Current status of intestinal and multivisceral transplantation. Gastroenterol Rep (Oxf) 2017; 5:20-28. [PMID: 28130374 PMCID: PMC5444259 DOI: 10.1093/gastro/gow045] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Clinical-nutritional autonomy is the ultimate goal of patients with intestinal failure (IF). Traditionally, patients with IF have been relegated to lifelong parenteral nutrition (PN) once surgical and medical rehabilitation attempts at intestinal adaptation have failed. Over the past two decades, however, outcome improvements in intestinal transplantation have added another dimension to the therapeutic armamentarium in the field of gut rehabilitation. This has become possible through relentless efforts in the standardization of surgical techniques, advancements in immunosuppressive therapies and induction protocols and improvement in postoperative patient care. Four types of intestinal transplants include isolated small bowel transplant, liver-small bowel transplant, multivisceral transplant and modified multivisceral transplant. Current guidelines restrict intestinal transplantation to patients who have had significant complications from PN including liver failure and repeated infections. From an experimental stage to the currently established therapeutic modality for patients with advanced IF, outcome improvements have also been possible due to the introduction of tacrolimus in the early 1990s. Studies have shown that intestinal transplant is cost-effective within 1-3 years of graft survival compared with PN. Improved survival and quality of life as well as resumption of an oral diet should enable intestinal transplantation to be an important option for patients with IF in addition to continued rehabilitation. Future research should focus on detecting biomarkers of early rejection, enhanced immunosuppression protocols, improved postoperative care and early referral to transplant centers.
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Affiliation(s)
- Shishira Bharadwaj
- Center for Gut Rehabilitation and Transplantation, the Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Parul Tandon
- Center for Gut Rehabilitation and Transplantation, the Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Tushar D Gohel
- Center for Gut Rehabilitation and Transplantation, the Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Jill Brown
- Center for Gut Rehabilitation and Transplantation, the Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Ezra Steiger
- Center for Gut Rehabilitation and Transplantation, the Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Donald F Kirby
- Center for Gut Rehabilitation and Transplantation, the Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Ajai Khanna
- Center for Gut Rehabilitation and Transplantation, the Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Kareem Abu-Elmagd
- Center for Gut Rehabilitation and Transplantation, the Cleveland Clinic Foundation, Cleveland, OH, USA
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Hashimoto K, Costa G, Khanna A, Fujiki M, Quintini C, Abu-Elmagd K. Recent Advances in Intestinal and Multivisceral Transplantation. Adv Surg 2016; 49:31-63. [PMID: 26299489 DOI: 10.1016/j.yasu.2015.04.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Koji Hashimoto
- Center for Gut Rehabilitation and Transplantation, Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Guilherme Costa
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15261, USA
| | - Ajai Khanna
- Center for Gut Rehabilitation and Transplantation, Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Masato Fujiki
- Center for Gut Rehabilitation and Transplantation, Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Cristiano Quintini
- Center for Gut Rehabilitation and Transplantation, Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Kareem Abu-Elmagd
- Center for Gut Rehabilitation and Transplantation, Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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18
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Li X, Wang X, Jiang H, Zhang G, Tan R, Sun Y, Wu X, Tan R, Xu Q. Herpetol ameliorates allergic contact dermatitis through regulating T-lymphocytes. Int Immunopharmacol 2016; 40:131-138. [DOI: 10.1016/j.intimp.2016.08.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 08/23/2016] [Accepted: 08/23/2016] [Indexed: 01/16/2023]
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Adams AB, Newell KA. Transplantation tolerance: Coming of age. Hepatology 2016; 64:347-9. [PMID: 26991323 DOI: 10.1002/hep.28553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 03/09/2016] [Indexed: 12/27/2022]
Affiliation(s)
- Andrew B Adams
- Emory Transplant Center, Emory University School of Medicine, Atlanta, GA
| | - Kenneth A Newell
- Emory Transplant Center, Emory University School of Medicine, Atlanta, GA
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Flynn B, Park BK, Bond G, McGhee W, Mazariegos G, Sindhi R, Reyes J, Abu-Elmagd K. Immunosuppressant Strategies for Intestinal Transplantation: A Review of a Tolerogenic Regimen. Prog Transplant 2016; 15:60-4. [PMID: 15839373 DOI: 10.1177/152692480501500110] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Intestinal, combined liver-intestinal, and multivisceral transplantation are now considered the standard of care for children and adults with permanent intestinal failure. Early attempts at intestinal transplantation were discouraging because of the high incidence of technical complications, rejection, and infection. Advances in the field of transplantation, including the introduction of tacrolimus, improved surgical techniques, and improvements in postoperative care, have led to a renewed interest in intestinal transplantation since 1990. The most significant achievement, however, has been the effective control of rejection and life-threatening infections. This article focuses on the experience to date of innovative strategies that induce lymphocyte depletion and reduction in the incidence of rejection. In this setting, low-maintenance immunosuppression is clinically achievable with an acceptable rate of allograft rejection. Subsequently, the long-term complications of immunosuppression are significantly reduced with achievement of better long-term survival, and an overall improvement in the quality of life.
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Affiliation(s)
- Bridget Flynn
- University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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Chang CC, Chen SCA. Colliding Epidemics and the Rise of Cryptococcosis. J Fungi (Basel) 2015; 2:jof2010001. [PMID: 29376920 PMCID: PMC5753082 DOI: 10.3390/jof2010001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 11/18/2015] [Accepted: 12/09/2015] [Indexed: 12/15/2022] Open
Abstract
Discovered more than 100 years ago as a human pathogen, the Cryptococcus neoformans–Cryptococcus gattii (C. neoformans–C. gattii) complex has seen a large global resurgence in its association with clinical disease in the last 30 years. First isolated in fermenting peach juice, and identified as a human pathogen in 1894 in a patient with bone lesions, this environmental pathogen has now found niches in soil, trees, birds, and domestic pets. Cryptococcosis is well recognized as an opportunistic infection and was first noted to be associated with reticuloendothelial cancers in the 1950s. Since then, advances in transplant immunology, medical science and surgical techniques have led to increasing numbers of solid organ transplantations (SOT) and hematological stem cell transplantations being performed, and the use of biological immunotherapeutics in increasingly high-risk and older individuals, have contributed to the further rise in cryptococcosis. Globally, however, the major driver for revivification of cryptococcosis is undoubtedly the HIV epidemic, particularly in Sub-Saharan Africa where access to care and antiretroviral therapy remains limited and advanced immunodeficiency, poverty and malnutrition remains the norm. As a zoonotic disease, environmental outbreaks of both human and animal cryptococcosis have been reported, possibly driven by climate change. This is best exemplified by the resurgence of C. gattii infection in Vancouver Island, Canada, and the Pacific Northwest of the United States since 1999. Here we describe how the colliding epidemics of HIV, transplantation and immunologics, climate change and migration have contributed to the rise of cryptococcosis.
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Affiliation(s)
- Christina C Chang
- Department of Infectious Diseases, Alfred Hospital, Monash University, Melbourne 3181, Australia.
- HIV Pathogenesis Programme, University of KwaZulu Natal, Durban 4001, South Africa.
| | - Sharon C-A Chen
- Marie Bashir Institute for Emerging Infectious Diseases and Biosecurity, University of Sydney, Sydney 2145, Australia.
- Centre for Infectious Diseases and Microbiology Laboratory Services, ICPMR-Pathology West, Westmead Hospital, Sydney 2145, Australia.
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22
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Starzl TE. Anthony Cerami Award in Translational Medicine: A Journey in Science: The Birth of Organ Transplantation with Particular Reference to Alloengraftment Mechanisms. Mol Med 2015; 21:227-32. [PMID: 26197024 PMCID: PMC4503646 DOI: 10.2119/molmed.2014.00254] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 12/16/2014] [Indexed: 11/06/2022] Open
Affiliation(s)
- Thomas E Starzl
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
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Baron D, Giral M, Brouard S. Reconsidering the detection of tolerance to individualize immunosuppression minimization and to improve long-term kidney graft outcomes. Transpl Int 2015; 28:938-59. [DOI: 10.1111/tri.12578] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 02/03/2015] [Accepted: 04/02/2015] [Indexed: 01/03/2023]
Affiliation(s)
- Daniel Baron
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Magali Giral
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Sophie Brouard
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
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Hall BM. T Cells: Soldiers and Spies--The Surveillance and Control of Effector T Cells by Regulatory T Cells. Clin J Am Soc Nephrol 2015; 10:2050-64. [PMID: 25876770 DOI: 10.2215/cjn.06620714] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Traditionally, T cells were CD4+ helper or CD8+ cytotoxic T cells, and with antibodies, they were the soldiers of immunity. Now, many functionally distinct subsets of activated CD4+ and CD8+ T cells have been described, each with distinct cytokine and transcription factor expression. For CD4+ T cells, these include Th1 cells expressing the transcription factor T-bet and cytokines IL-2, IFN-γ, and TNF-β; Th2 cells expressing GATA-3 and the cytokines IL-4, IL-5, and IL-13; and Th17 cells expressing RORγt and cytokines IL-17A, IL-17F, IL-21, and IL-22. The cytokines produced determine the immune inflammation that they mediate. T cells of the effector lineage can be naïve T cells, recently activated T cells, or memory T cells that can be distinguished by cell surface markers. T regulatory cells or spies were characterized as CD8+ T cells expressing I-J in the 1970s. In the 1980s, suppressor cells fell into disrepute when the gene for I-J was not present in the mouse MHC I region. At that time, a CD4+ T cell expressing CD25, the IL-2 receptor-α, was identified to transfer transplant tolerance. This was the same phenotype of activated CD4+ CD25+ T cells that mediated rejection. Thus, the cells that could induce tolerance and undermine rejection had similar badges and uniforms as the cells effecting rejection. Later, FOXP3, a transcription factor that confers suppressor function, was described and distinguishes T regulatory cells from effector T cells. Many subtypes of T regulatory cells can be characterized by different expressions of cytokines and receptors for cytokines or chemokines. In intense immune inflammation, T regulatory cells express cytokines characteristic of effector cells; for example, Th1-like T regulatory cells express T-bet, and IFN-γ-like Th1 cells and effector T cells can change sides by converting to T regulatory cells. Effector T cells and T regulatory cells use similar molecules to be activated and mediate their function, and thus, it can be very difficult to distinguish soldiers from spies.
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Affiliation(s)
- Bruce M Hall
- Immune Tolerance Laboratory, Department of Medicine, University of New South Wales, Sydney, Australia; and Renal Unit, Liverpool Hospital, Sydney, Australia
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Abu-Elmagd K. The concept of gut rehabilitation and the future of visceral transplantation. Nat Rev Gastroenterol Hepatol 2015; 12:108-20. [PMID: 25601664 DOI: 10.1038/nrgastro.2014.216] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In the 1990s, the introduction of visceral transplantation fuelled interest in other innovative therapeutic modalities for gut rehabilitation. Ethanol lock and omega-3 lipid formulations were introduced to reduce the risks associated with total parenteral nutrition (TPN). Autologous surgical reconstruction and bowel lengthening have been increasingly utilized for patients with complex abdominal pathology and short-bowel syndrome. Glucagon-like peptide 2 analogue, along with growth hormone, are available to enhance gut adaptation and achieve nutritional autonomy. Intestinal transplantation continues to be limited to a rescue therapy for patients with TPN failure. Nonetheless, survival outcomes have substantially improved with advances in surgical techniques, immunosuppressive strategies and postoperative management. Furthermore, both nutritional autonomy and quality of life can be restored for more than two decades in most survivors, with social support and inclusion of the liver being favourable predictors of long-term outcome. One of the current challenges is the discovery of biomarkers to diagnose early rejection and further improve liver-free allograft survival. Currently, chronic rejection with persistence of preformed and development of de novo donor-specific antibodies is a major barrier to long-term graft function; this issue might be overcome with innovative immunological and tolerogenic strategies. This Review discusses advances in the field of gut rehabilitation, including intestinal transplantation, and highlights future challenges. With the growing interest in individualized medicine and the value of health care, a novel management algorithm is proposed to optimize patient care through an integrated multidisciplinary team approach.
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Affiliation(s)
- Kareem Abu-Elmagd
- Transplant Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
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Delayed introduction of tacrolimus postliver transplant with intravenous mycophenolate mofetil preserves renal function without incurring rejection. Transplantation 2014; 98:e68-70. [PMID: 25285953 DOI: 10.1097/tp.0000000000000371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
Advances in pharmacologic immunosuppression are responsible for the excellent outcomes experienced by recipients of liver transplants. However, long-term follow-up of these patients reveals an increasing burden of morbidity and mortality that is attributable to these drugs. The authors summarize the agents used in contemporary liver transplantation immunosuppression protocols and discuss the emerging trend within the community to minimize or eliminate these agents from use. The authors present recently published data that may provide the foundation for immunosuppression minimization or tolerance induction in the future and review studies that have focused on the utility of biomarkers in guiding immunosuppression management.
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Kochat V, Baligar P, Maiwall R, Mukhopadhyay A. Bone marrow stem-cell therapy for genetic and chronic liver diseases. Hepatol Int 2014. [DOI: 10.1007/s12072-013-9499-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Meier D, Rumbo M, Gondolesi GE. Current Status of Allograft Tolerance in Intestinal Transplantation. Int Rev Immunol 2013; 33:245-60. [DOI: 10.3109/08830185.2013.829468] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Wu SL, Pan CE. Tolerance and chimerism and allogeneic bone marrow/stem cell transplantation in liver transplantation. World J Gastroenterol 2013; 19:5981-7. [PMID: 24106398 PMCID: PMC3785619 DOI: 10.3748/wjg.v19.i36.5981] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 06/05/2013] [Accepted: 07/18/2013] [Indexed: 02/06/2023] Open
Abstract
The liver has particular tolerogenic properties that allow its spontaneous acceptance in some animal species. Liver structure is considered to favor a tolerogenic environment. The peripheral tolerance mechanisms also play a role in spontaneous tolerance to liver graft. In a clinical setting, the main challenge nowadays facing liver transplantation is minimization of immunosuppression with the goal of donor-specific tolerance. Mechanisms involved in tolerance to transplanted organs are complex and partly unknown. A significant mechanism in tolerance induction is chimerism. Chimerism can be induced through transplantation of allogeneic donor bone marrow/stem cells under appropriate host conditioning. This review focuses on the tolerance mechanisms in liver transplantation and highlights the role of chimerism and allogeneic bone marrow/stem cell transplantation in tolerance development.
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Kilinc S, Tan S, Kolatan EH, Ruscuklu D, Satici E, Kemiksiz M, Dalkilic L, Erdogdu UE, Karaca C. The effects of preoperative immunosuppressive therapy on ischemia and reperfusion (I/R) injury in healthy rats. Int Urol Nephrol 2013; 46:389-93. [PMID: 24014133 DOI: 10.1007/s11255-013-0548-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 05/14/2013] [Indexed: 01/09/2023]
Abstract
PURPOSE Warm-ischemia-induced injuries might be encountered during renal transplants from cadavers and healthy donors. Toll-like receptors (TLR) in ischemia-reperfusion (I/R) injury are one of the indicators of intracellular injury pathways. The intensity of ischemic injury is directly proportionate to high TLR levels. To minimize the I/R injury, we investigated TLR2 and TLR4 levels on rats, which were pretreated with tacrolimus (FK506) before I/R. METHODS Eight Wistar albino rats in the study group were administered .01 mg/kg intramuscular tacrolimus. Administration to the study group was performed 24 and 1 h before warm ischemia. Eight rats in the control group were injected with 0.1 c.c. of distilled water. Blood samples were collected from the tail veins of all the rats on the first, second and third days. Expression levels of TLR2 and TLR4 genes were analyzed using the polymerase chain reaction method, to determine any significant difference between the control and study groups on the days when blood was taken. RESULTS TLR2 (p = 0.045) and TLR4 (p = 0.022) levels in the study group were found to be statistically, and significantly, lower than those in the control group, on the second day following warm-ischemia- and reperfusion-induced injury. CONCLUSIONS Administration of immunosuppressive drugs to healthy donor rats led to a statistically significant reduction in the expression levels of TLR2 and TLR4 in the early period. In light of the data obtained by this study, we hypothesize that a preoperative therapy on donors might have a role in preventing I/R injury.
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Affiliation(s)
- Selcuk Kilinc
- İzmir Tepecik Training and Research Hospital Transplant Department, Izmir, Turkey
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Abstract
OBJECTIVE To minimize maintenance immunosuppression in upper-extremity transplantation to favor the risk-benefit balance of this procedure. BACKGROUND Despite favorable outcomes, broad clinical application of reconstructive transplantation is limited by the risks and side effects of multidrug immunosuppression. We present our experience with upper-extremity transplantation under a novel, donor bone marrow (BM) cell-based treatment protocol ("Pittsburgh protocol"). METHODS Between March 2009 and September 2010, 5 patients received a bilateral hand (n = 2), a bilateral hand/forearm (n = 1), or a unilateral (n = 2) hand transplant. Patients were treated with alemtuzumab and methylprednisolone for induction, followed by tacrolimus monotherapy. On day 14, patients received an infusion of donor BM cells isolated from 9 vertebral bodies. Comprehensive follow-up included functional evaluation, imaging, and immunomonitoring. RESULTS All patients are maintained on tacrolimus monotherapy with trough levels ranging between 4 and 12 ng/mL. Skin rejections were infrequent and reversible. Patients demonstrated sustained improvements in motor function and sensory return correlating with time after transplantation and level of amputation. Side effects included transient increase in serum creatinine, hyperglycemia managed with oral hypoglycemics, minor wound infection, and hyperuricemia but no infections. Immunomonitoring revealed transient moderate levels of donor-specific antibodies, adequate immunocompetence, and no peripheral blood chimerism. Imaging demonstrated patent vessels with only mild luminal narrowing/occlusion in 1 case. Protocol skin biopsies showed absent or minimal perivascular cellular infiltrates. CONCLUSIONS Our data suggest that this BM cell-based treatment protocol is safe, is well tolerated, and allows upper-extremity transplantation using low-dose tacrolimus monotherapy.
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Abstract
Composite tissue transplantation is an emerging new era in transplant medicine and has become a viable reconstructive option for patients with large and devastating tissue defects. Advances in microsurgical techniques, transplant immunology and the development of potent immunosuppressive agents have enabled the realization of such types of transplants. Over the past decade, a rapidly growing number of face and upper extremity transplantations have been performed worldwide with highly encouraging outcomes. However, despite the fact that surgical, immunological and functional results are highly encouraging, the need for long-term and high-dose immunosuppression to enable graft survival and to treat/reverse acute skin rejection episodes remains a pace-limiting obstacle towards wide spread application. In this chapter we review the history and development of this novel field, the functional and immunological outcomes based on the world experience, unique biological features of such transplants, mechanisms and treatment protocols for acute skin rejection, as well as novel concepts for immune modulation and tolerance induction.
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Affiliation(s)
- Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Ravindra KV, Xu H, Bozulic LD, Song DD, Ildstad ST. The need for inducing tolerance in vascularized composite allotransplantation. Clin Dev Immunol 2012; 2012:438078. [PMID: 23251216 PMCID: PMC3509522 DOI: 10.1155/2012/438078] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 09/14/2012] [Indexed: 11/24/2022]
Abstract
Successful hand and face transplantation in the last decade has firmly established the field of vascularized composite allotransplantation (VCA). The experience in VCA has thus far been very similar to solid organ transplantation in terms of the morbidity associated with long-term immunosuppression. The unique immunological features of VCA such as split tolerance and resistance to chronic rejection are being investigated. Simultaneously there has been laboratory work studying tolerogenic protocols in animal VCA models. In order to optimize VCA outcomes, translational studies are needed to develop less toxic immunosuppression and possibly achieve donor-specific tolerance. This article reviews the immunology, animal models, mixed chimerism & tolerance induction in VCA and the direction of future research to enable better understanding and wider application of VCA.
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Affiliation(s)
- Kadiyala V. Ravindra
- Department of Surgery, Duke University Medical Center (DUMC) 3512, Durham, NC 27710, USA
| | - Hong Xu
- Institute for Cellular Therapeutics and Jewish Hospital, University of Louisville, 570 South Preston Street, Suite 404, Louisville, KY 40202-1760, USA
| | - Larry D. Bozulic
- Institute for Cellular Therapeutics and Jewish Hospital, University of Louisville, 570 South Preston Street, Suite 404, Louisville, KY 40202-1760, USA
| | - David D. Song
- Institute for Cellular Therapeutics and Jewish Hospital, University of Louisville, 570 South Preston Street, Suite 404, Louisville, KY 40202-1760, USA
| | - Suzanne T. Ildstad
- Institute for Cellular Therapeutics and Jewish Hospital, University of Louisville, 570 South Preston Street, Suite 404, Louisville, KY 40202-1760, USA
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Gorantla VS, Brandacher G, Schneeberger S, Zheng XX, Donnenberg AD, Losee JE, Lee WPA. Favoring the risk-benefit balance for upper extremity transplantation--the Pittsburgh Protocol. Hand Clin 2011; 27:511-20, ix-x. [PMID: 22051391 DOI: 10.1016/j.hcl.2011.08.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Upper extremity transplantation is an innovative reconstructive strategy with potential of immediate clinical application and the most near-term pay-off for select amputees, allowing reintegration into employment and society. Routine applicability and widespread impact of such strategies for the upper extremity amputees with devastating limb loss could be enabled by implementation of cellular therapies that integrate and unify the concepts of transplant tolerance induction with those of reconstructive transplantation. Such therapies offer the promise of minimizing the risks, maximizing the benefits and optimizing outcomes of these innovative procedures.
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Affiliation(s)
- Vijay S Gorantla
- Pittsburgh Reconstructive Transplantation Program, Division of Plastic Surgery, Department of Surgery, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
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Cippà PE, Fehr T. Spontaneous tolerance in kidney transplantation--an instructive, but very rare paradigm. Transpl Int 2011; 24:534-5. [PMID: 21535235 DOI: 10.1111/j.1432-2277.2011.01260.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Pietro E Cippà
- Division of Nephrology, University Hospital Zürich, Rämistrasse 100, Zürich, Switzerland
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Five hundred intestinal and multivisceral transplantations at a single center: major advances with new challenges. Ann Surg 2011; 250:567-81. [PMID: 19730240 DOI: 10.1097/sla.0b013e3181b67725] [Citation(s) in RCA: 262] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To assess the evolution of visceral transplantation in the milieu of surgical technical modifications, new immunosuppressive protocols, and other management strategies. SUMMARY BACKGROUND DATA With the clinical feasibility of intestinal and multivisceral transplantation in 1990, multifaceted innovative tactics were required to improve outcome and increase procedural practicality. METHODS Divided into 3 eras, 453 patients received 500 visceral transplants. The primary used immunosuppression was tacrolimus-steroid-only during Era I (5/90–5/94), adjunct induction with multiple drug therapy during Era II (1/95–6/01), and recipient pretreatment with tacrolimus monotherapy during Era III (7/01–11/08). During Era II/III, donor bone marrow was given (n = 79), intestine was ex vivo irradiated (n = 44), and Epstein-Barr-Virus (EBV)/cytomegalovirus (CMV) loads were monitored. RESULTS Actuarial patient survival was 85% at 1-year, 61% at 5-years, 42% at 10-years, and 35% at 15-years with respective graft survival of 80%, 50%, 33%, and 29%. With a 10% retransplantation rate, second/third graft survival was 69% at 1-year and 47% at 5-years. The best outcome was with intestine-liver allografts. Era III rabbit antithymocyte globulin or alemtuzumab pretreatment-based strategy was associated with significant (P < 0.0001) improvement in outcome with 1- and 5-year patient survival of 92% and 70%. CONCLUSION Survival has greatly improved over time as management strategies evolved. The current results clearly justify elevating the procedure level to that of other abdominal organs with the privilege to permanently reside in a respected place in the surgical armamentarium. Meanwhile, innovative tactics are still required to conquer long-term hazards of chronic rejection of liver-free allografts and infection of multivisceral recipients.
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Orlando G. Finding the right time for weaning off immunosuppression in solid organ transplant recipients. Expert Rev Clin Immunol 2011; 6:879-92. [PMID: 20979553 DOI: 10.1586/eci.10.71] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Solid organ transplantation (SOT) requires lifelong immunosuppression (IS) to prevent rejection and graft loss. The currently adopted immunosuppressive protocols are numerous and are based on the administration of at least two molecules with diverse mechanisms of action. Owing to the fact that the majority of immunosuppressants act non-selectively, the immune system is normally oversuppressed, and as a result is less able to both defend the host against infection and to control the spread of malignant cells. Consequently, long-term IS is burdened by chronic toxicity, which may be highly invalidating and may significantly influence patient's quality of life, compliance to treatment, overall success rate, and patient and graft survival. In an ideal scenario, SOT recipients should initially receive just enough IS to favor the onset of clinical operational tolerance (COT), a condition where the immune system of the host does not attack the graft in the absence of any immunosuppressant. COT has been documented after liver transplantation (LT) and renal transplantation (RT). First, COT was accidentally detected in patients who were nonadherent to treatment and who spontaneously decided to stop all IS without any medical guidance or surveillance. Later, it was described in recipients who required IS withdrawal following the occurrence of malignant diseases. Based on strikingly convincing experimental data, several tolerogenic protocols have recently been applied in patients but overall the results have been disappointing. The current literature demonstrates that COT can be safely achieved in stable LT recipients, with completely different strategies. Importantly, the onset of an episode of acute rejection during the attempt of IS withdrawal would not worsen the clinical outcome. On the contrary, COT remains a major challenge after RT because the onset of acute rejection will substantiate in graft loss. Currently, a major field of investigation aims to define markers of COT, which will allow the selection of individuals who are more prone to develop COT. Preliminary results in both RT and LT have just been announced; however, these markers will require validation in prospective studies.
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Affiliation(s)
- Giuseppe Orlando
- Nuffield Department of Surgery, University of Oxford, Oxford, UK.
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Nayyar NS, McGhee W, Martin D, Sindhi R, Soltys K, Bond G, Mazariegos GV. Intestinal transplantation in children: a review of immunotherapy regimens. Paediatr Drugs 2011; 13:149-59. [PMID: 21500869 PMCID: PMC7101554 DOI: 10.2165/11588530-000000000-00000] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
This review summarizes the outcomes and known adverse effects of current immunosuppression strategies in use in pediatric intestinal transplantation. Intestinal transplantation has evolved from an experimental therapy to a highly successful treatment for children with intestinal failure who have complications with total parenteral nutrition. Because of continued success with intestinal transplantation over the past decade, the focus of clinicians and researchers is shifting from short-term patient survival to optimizing long-term outcomes. Current 5-year patient and graft survival rates after intestinal transplantation are 58% and 40%, respectively, in the US; single centers have reported nearly 80% patient and 60% graft survival rates at 5 years. The immunosuppression strategy in intestinal transplantation includes a tacrolimus-based regimen, usually in conjunction with an antibody induction therapy such as rabbit-antithymocyte globulin, interleukin-2 receptor antagonists, or alemtuzumab. The use of these immunosuppressive regimens, along with improved medical and surgical care, has contributed significantly toward improved outcomes. Optimization of post-transplant immunosuppression strategies to reduce adverse effects while minimizing acute and chronic graft rejection is a strong clinical and research focus.
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Affiliation(s)
- Navdeep S. Nayyar
- Hillman Center for Pediatric Transplantation, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Faculty Pavilion, Floor 6, Pittsburgh, Pennsylvania 15224 USA
| | - William McGhee
- Thomas E. Starzl Transplantation Institute, Pittsburgh, Pennsylvania USA ,Department of Pharmacy, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania USA
| | - Dolly Martin
- Thomas E. Starzl Transplantation Institute, Pittsburgh, Pennsylvania USA
| | - Rakesh Sindhi
- Hillman Center for Pediatric Transplantation, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Faculty Pavilion, Floor 6, Pittsburgh, Pennsylvania 15224 USA ,Thomas E. Starzl Transplantation Institute, Pittsburgh, Pennsylvania USA
| | - Kyle Soltys
- Hillman Center for Pediatric Transplantation, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Faculty Pavilion, Floor 6, Pittsburgh, Pennsylvania 15224 USA ,Thomas E. Starzl Transplantation Institute, Pittsburgh, Pennsylvania USA
| | - Geoffrey Bond
- Hillman Center for Pediatric Transplantation, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Faculty Pavilion, Floor 6, Pittsburgh, Pennsylvania 15224 USA ,Thomas E. Starzl Transplantation Institute, Pittsburgh, Pennsylvania USA
| | - George V. Mazariegos
- Hillman Center for Pediatric Transplantation, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Faculty Pavilion, Floor 6, Pittsburgh, Pennsylvania 15224 USA ,Thomas E. Starzl Transplantation Institute, Pittsburgh, Pennsylvania USA
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Benítez CE, Puig-Pey I, López M, Martínez-Llordella M, Lozano JJ, Bohne F, Londoño MC, García-Valdecasas JC, Bruguera M, Navasa M, Rimola A, Sánchez-Fueyo A. ATG-Fresenius treatment and low-dose tacrolimus: results of a randomized controlled trial in liver transplantation. Am J Transplant 2010; 10:2296-304. [PMID: 20883560 DOI: 10.1111/j.1600-6143.2010.03164.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We report the results of a prospective randomized controlled trial in liver transplantation assessing the efficacy and safety of antithymocyte globulin (ATG-Fresenius) plus tacrolimus monotherapy at gradually decreasing doses. Patients were randomized to either: (a) standard-dose tacrolimus plus steroids;or (b) peritransplant ATG-Fresenius plus reduced-dose tacrolimus monotherapy followed by weaning of tacrolimus starting 3 months after transplantation. The primary end-point was the achievement of very low-dose tacrolimus (every-other-day or once daily dose with <5 ng/mL trough levels) at 12 months after transplantation. Acute rejection occurring during the first 3 months after transplantation was more frequent in the ATG group (52.4% vs. 25%). Moreover, late acute rejection episodes occurred in all recipients in whom weaning was attempted and no recipients reached the primary end-point. This motivated the premature termination of the trial. Tacrolimus trough levels were lower in the ATG-Fresenius group but no benefits in terms of improved renal function, lower metabolic complications or increased prevalence of tolerance-related biomarkers were observed. In conclusion, the use of ATG-Fresenius and tacrolimus at gradually decreasing doses was associated with a high rate of rejection, did not allow for the administration of very low doses of tacrolimus and failed to provide detectable clinical benefits. ClinicalTrials.gov identifier: NCT00436722.
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Affiliation(s)
- C E Benítez
- Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain
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Abstract
The past few decades are characterized by an explosive evolution of genetics and molecular cell biology. Advances in chemistry and engineering have enabled increased data throughput, permitting the study of complete sets of molecules with increasing speed and accuracy using techniques such as genomics, transcriptomics, proteomics, and metabolomics. Prediction of long-term outcomes in transplantation is hampered by the absence of sufficiently robust biomarkers and a lack of adequate insight into the mechanisms of acute and chronic alloimmune injury and the adaptive mechanisms of immunological quiescence that may support transplantation tolerance. Here, we discuss some of the great opportunities that molecular diagnostic tools have to offer both basic scientists and translational researchers for bench-to-bedside clinical application in transplantation medicine, with special focus on genomics and genome-wide association studies, epigenetics (DNA methylation and histone modifications), gene expression studies and transcriptomics (including microRNA and small interfering RNA studies), proteomics and peptidomics, antibodyomics, metabolomics, chemical genomics and functional imaging with nanoparticles. We address the challenges and opportunities associated with the newer high-throughput sequencing technologies, especially in the field of bioinformatics and biostatistics, and demonstrate the importance of integrative approaches. Although this Review focuses on transplantation research and clinical transplantation, the concepts addressed are valid for all translational research.
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Abstract
Liver transplantation was the product of five interlocking themes. These began in 1958-1959 with canine studies of then theoretical hepatotrophic molecules in portal venous blood (Theme I) and with the contemporaneous parallel development of liver and multivisceral transplant models (Theme II). Further Theme I investigations showed that insulin was the principal, although not the only, portal hepatotrophic factor. In addition to resolving long-standing controversies about the pathophysiology of portacaval shunt, the hepatotrophic studies blazed new trails in the regulation of liver size, function, and regeneration. They also targeted inborn metabolic errors (e.g., familial hyperlipoproteinemia) whose palliation by portal diversion presaged definitive correction with liver replacement. Clinical use of the Theme II transplant models depended on multiple drug immunosuppression (Theme III, Immunology), guided by an empirical algorithm of pattern recognition and therapeutic response. Successful liver replacement was first accomplished in 1967 with azathioprine, prednisone, and antilymphoid globulin. With this regimen, the world's longest surviving liver recipient is now 40 years postoperative. Incremental improvements in survival outcome occurred (Theme IV) when azathioprine was replaced by cyclosporine (1979), which was replaced in turn by tacrolimus (1989). However, the biologic meaning of alloengraftment remained enigmatic until multilineage donor leukocyte microchimerism was discovered in 1992 in long-surviving organ recipients. Seminal mechanisms were then identified (clonal exhaustion-deletion and immune ignorance) that linked organ engraftment and the acquired tolerance of bone marrow transplantation and eventually clarified the relationship of transplantation immunology to the immunology of infections, neoplasms, and autoimmune disorders. With this insight, better strategies of immunosuppression have evolved. As liver and other kinds of organ transplantation became accepted as healthcare standards, the ethical, legal, equity, and the other humanism issues of Theme V have been resolved less conclusively than the medical-scientific problems of Themes I-IV.
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Affiliation(s)
- Thomas E. Starzl
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213
| | - John J. Fung
- Department of Surgery, Cleveland Clinic, Cleveland, Ohio 44195
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Li F, Huang Q, Chen J, Peng Y, Roop DR, Bedford JS, Li CY. Apoptotic cells activate the "phoenix rising" pathway to promote wound healing and tissue regeneration. Sci Signal 2010; 3:ra13. [PMID: 20179271 DOI: 10.1126/scisignal.2000634] [Citation(s) in RCA: 367] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The ability to regenerate damaged tissues is a common characteristic of multicellular organisms. We report a role for apoptotic cell death in promoting wound healing and tissue regeneration in mice. Apoptotic cells released growth signals that stimulated the proliferation of progenitor or stem cells. Key players in this process were caspases 3 and 7, proteases activated during the execution phase of apoptosis that contribute to cell death. Mice lacking either of these caspases were deficient in skin wound healing and in liver regeneration. Prostaglandin E(2), a promoter of stem or progenitor cell proliferation and tissue regeneration, acted downstream of the caspases. We propose to call the pathway by which executioner caspases in apoptotic cells promote wound healing and tissue regeneration in multicellular organisms the "phoenix rising" pathway.
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Affiliation(s)
- Fang Li
- Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO 80045, USA
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Thangavelu G, Smolarchuk C, Anderson CC. Co-inhibitory molecules: Controlling the effectors or controlling the controllers? SELF NONSELF 2010; 1:77-88. [PMID: 21487510 DOI: 10.4161/self.1.2.11548] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2010] [Revised: 02/15/2010] [Accepted: 02/16/2010] [Indexed: 12/31/2022]
Abstract
Nearly forty years ago the concept was proposed that lymphocytes are negatively regulated by what are now called co-inhibitory signals. Nevertheless, it is only the more recent identification of numerous co-inhibitors and their critical functions that has brought co-inhibition to the forefront of immunologic research. Although co-inhibitory signals have been considered to directly regulate conventional T cells, more recent data has indicated a convergence between co-inhibitory signals and the other major negative control mechanism in the periphery that is mediated by regulatory T cells. Furthermore, it is now clear that lymphocytes are not the sole domain of co-inhibitory signals, as cells of the innate immune system, themselves controllers of immunity, are regulated by co-inhibitors they express. Thus, in order to better understand negative regulation in the periphery and apply this knowledge to the treatment of disease, a major focus for the future should be the definition of the conditions where co-inhibition controls effector cells intrinsically versus extrinsically (via regulatory or innate cells).
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Affiliation(s)
- Govindarajan Thangavelu
- Department of Surgery; Alberta Diabetes Institute; University of Alberta; Edmonton, Alberta Canada
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Xu M, Tan C, Zhou J, Huang X, Dai Z, Zhu H, Zhao Y, Gu F, Zhou S, Fan J. The dynamic changes of T-bet+/GATA-3+ and RORγt+/FOXP3+ cells in recipient spleens and grafts after rat orthotopic liver transplantation. Transpl Immunol 2010; 22:165-71. [DOI: 10.1016/j.trim.2009.11.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2009] [Revised: 10/27/2009] [Accepted: 11/02/2009] [Indexed: 12/17/2022]
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Ebrahimi M, Aghdami N. The applications of bone marrow-derived stem cells to induce tolerance and chimerism in organ transplantation. Int J Organ Transplant Med 2010; 1:157-69. [PMID: 25013581 PMCID: PMC4089239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Progress in understanding the cellular and molecular biology of the immune system, in the second half of the 20(th) century brings the transplantation of replacement organs and tissues in clinical reality to cure disease. Immunosuppressive agents that are part of nearly every transplantation procedure, are toxic to some extent and their chronic use predisposes the patient to the development of infection and cancer. Alternatives to immunosuppression include modulation of host immune system to reduce the immune response and the induction of a state of immunologic tolerance. Induction of hematopoietic mixed chimerism through donor bone marrow transplantation offers a promising approach for tolerance induction as a prelude to organ transplantation. Furthermore, mesenchymal stromal cells have important effects on the host immune system and possess immune modulation properties that make them attractive for potential use in organ transplantation as immunosuppressant. Both modalities might potentially provide novel therapeutic options for treatment/prevention of rejection and/or repair of organ allografts through their multifaceted properties. In this review, evidences for the tolerogenic properties and mechanisms of hematopoietic mixed chimerism as well as mesenchymal stromal cells effects on allograft surveillance are summarized.
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Affiliation(s)
| | - N. Aghdami
- Correspondence: Naser Aghdami, PhD, Department of Regenerative Medicine, Royan Institute for Stem Cell Biology and Technology, ACECR, PO Box 19395-4644, Tehran, Iran.
E-mail:
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Ravindra K, Wu S, McKinney M, Xu H, Ildstad S. Composite Tissue Allotransplantation: Current Challenges. Transplant Proc 2009; 41:3519-28. [DOI: 10.1016/j.transproceed.2009.08.052] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2009] [Accepted: 08/05/2009] [Indexed: 12/16/2022]
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Than NG, Kim SS, Abbas A, Han YM, Hotra J, Tarca AL, Erez O, Wildman DE, Kusanovic JP, Pineles B, Montenegro D, Edwin SS, Mazaki-Tovi S, Gotsch F, Espinoza J, Hassan SS, Papp Z, Romero R. Chorioamnionitis and increased galectin-1 expression in PPROM --an anti-inflammatory response in the fetal membranes? Am J Reprod Immunol 2009; 60:298-311. [PMID: 18691335 DOI: 10.1111/j.1600-0897.2008.00624.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
PROBLEM Galectin-1 can regulate immune responses upon infection and inflammation. We determined galectin-1 expression in the chorioamniotic membranes and its changes during histological chorioamnionitis. METHOD OF STUDY Chorioamniotic membranes were obtained from women with normal pregnancy (n = 5) and from patients with pre-term pre-labor rupture of the membranes (PPROM) with (n = 8) and without histological chorioamnionitis (n = 8). Galectin-1 mRNA and protein were localized by in situ hybridization and immunohistochemistry. Galectin-1 mRNA expression was also determined by quantitative reverse transcriptase polymerase chain reaction. RESULTS Galectin-1 mRNA and protein were detected in the amniotic epithelium, chorioamniotic fibroblasts/myofibroblasts and macrophages, chorionic trophoblasts, and decidual stromal cells. In patients with PPROM, galectin-1 mRNA expression in the fetal membranes was higher (2.07-fold, P = 0.002) in those with chorioamnionitis than in those without. Moreover, chorioamionitis was associated with a strong galectin-1 immunostaining in amniotic epithelium, chorioamniotic mesodermal cells, and apoptotic bodies. CONCLUSION Chorioamnionitis is associated with an increased galectin-1 mRNA expression and strong immunoreactivity of the chorioamniotic membranes; thus, galectin-1 may be involved in the regulation of the inflammatory responses to chorioamniotic infection.
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Affiliation(s)
- Nandor Gabor Than
- Perinatology Research Branch, NICHD/NIH/DHHS, Wayne State University/Hutzel Women's Hospital, 3990 John R, Box 4, Detroit, MI 48201, USA.
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Wu S, Xu H, Ravindra K, Ildstad ST. Composite tissue allotransplantation: past, present and future-the history and expanding applications of CTA as a new frontier in transplantation. Transplant Proc 2009; 41:463-5. [PMID: 19328904 DOI: 10.1016/j.transproceed.2009.01.027] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Composite tissue allotransplantation (CTA) transplantation is currently being performed with increasing frequency in the clinic. The feasibility of the procedure has been confirmed in over 40 successful hand transplants, 3 facial reconstructions, and vascularized knee, esophageal, abdominal wall, and tracheal allografts. The toxicity of chronic, nonspecific immunosuppression remains a major limitation to the widespread availability of CTA and is associated with opportunistic infections, nephrotoxicity, end-organ damage, and an increased rate of malignancy. Methods to reduce or eliminate the requirement for immunosuppression would represent a significant step forward in the field. Mixed chimerism induces tolerance to solid organ and tissue allografts, including CTA. This overview focuses on the history and expanding applications of CTA as a new frontier in transplantation, and considers the important hurdles that must be overcome through research to allow widespread clinical application.
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Affiliation(s)
- S Wu
- Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky, USA
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