Induction Phase of Spontaneous Liver Transplant Tolerance

McCaughan, Geoffrey W.; Bowen, David G.; Bertolino, Patrick

doi:10.3389/fimmu.2020.01908

Cited by 9 publications

(4 citation statements)

References 77 publications

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“…The best example is allogeneic liver allografts, which in some hosts are accepted without immunosuppression, reviewed ( 207 , 208 ). This was first observed with liver transplants in pigs ( 209 ), but also occurs in rats ( 211 ) and mice ( 210 ).…”

Section: Induction Of Transplant Tolerance In the Adults Specific Unr...mentioning

confidence: 99%

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Transplant Tolerance, Not Only Clonal Deletion

et al. 2022

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The quest to understand how allogeneic transplanted tissue is not rejected and how tolerance is induced led to fundamental concepts in immunology. First, we review the research that led to the Clonal Deletion theory in the late 1950s that has since dominated the field of immunology and transplantation. At that time many basic mechanisms of immune response were unknown, including the role of lymphocytes and T cells in rejection. These original observations are reassessed by considering T regulatory cells that are produced by thymus of neonates to prevent autoimmunity. Second, we review “operational tolerance” induced in adult rodents and larger animals such as pigs. This can occur spontaneously especially with liver allografts, but also can develop after short courses of a variety of rejection inhibiting therapies. Over time these animals develop alloantigen specific tolerance to the graft but retain the capacity to reject third-party grafts. These animals have a “split tolerance” as peripheral lymphocytes from these animals respond to donor alloantigen in graft versus host assays and in mixed lymphocyte cultures, indicating there is no clonal deletion. Investigation of this phenomenon excludes many mechanisms, including anti-donor antibody blocking rejection as well as anti-idiotypic responses mediated by antibody or T cells. This split tolerance is transferred to a second immune-depleted host by T cells that retain the capacity to effect rejection of third-party grafts by the same host. Third, we review research on alloantigen specific inhibitory T cells that led to the first identification of the CD4+CD25+T regulatory cell. The key role of T cell derived cytokines, other than IL-2, in promoting survival and expansion of antigen specific T regulatory cells that mediate transplant tolerance is reviewed. The precise methods for inducing and diagnosing operational tolerance remain to be defined, but antigen specific T regulatory cells are key mediators.

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Section: Induction Of Transplant Tolerance In the Adults Specific Unr...mentioning

confidence: 99%

“…The mass of the liver protects it from rejection. Activation of T cells by hepatocytes, rather than antigen presenting cells, leads to incomplete activation and rapid loss of function ( 208 ). High alloantigen expression in the liver exhausts alloantigen reactive CD8 + T cells ( 226 ).…”

Section: Induction Of Transplant Tolerance In the Adults Specific Unr...mentioning

confidence: 99%

Transplant Tolerance, Not Only Clonal Deletion

et al. 2022

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“…The liver is also considered a site in which T cells activated therein exhibit defective cytotoxic function ( 75 ), and a site of increased T cell apoptosis ( 76 ). Potential mechanisms that may mediate liver transplant tolerance have been reviewed recently ( 26 , 77 ).…”

Section: Liver Transplant Tolerancementioning

confidence: 99%

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection

et al. 2021

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Liver allograft recipients are more likely to develop transplantation tolerance than those that receive other types of organ graft. Experimental studies suggest that immune cells and other non-parenchymal cells in the unique liver microenvironment play critical roles in promoting liver tolerogenicity. Of these, liver interstitial dendritic cells (DCs) are heterogeneous, innate immune cells that appear to play pivotal roles in the instigation, integration and regulation of inflammatory responses after liver transplantation. Interstitial liver DCs (recruited in situ or derived from circulating precursors) have been implicated in regulation of both ischemia/reperfusion injury (IRI) and anti-donor immunity. Thus, livers transplanted from mice constitutively lacking DCs into syngeneic, wild-type recipients, display increased tissue injury, indicating a protective role of liver-resident donor DCs against transplant IRI. Also, donor DC depletion before transplant prevents mouse spontaneous liver allograft tolerance across major histocompatibility complex (MHC) barriers. On the other hand, mouse liver graft-infiltrating host DCs that acquire donor MHC antigen via “cross-dressing”, regulate anti-donor T cell reactivity in association with exhaustion of graft-infiltrating T cells and promote allograft tolerance. In an early phase clinical trial, infusion of donor-derived regulatory DCs (DCreg) before living donor liver transplantation can induce alterations in host T cell populations that may be conducive to attenuation of anti-donor immune reactivity. We discuss the role of DCs in regulation of warm and liver transplant IRI and the induction of liver allograft tolerance. We also address design of cell therapies using DCreg to reduce the immunosuppressive drug burden and promote clinical liver allograft tolerance.

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“…To avoid such long‐term adverse events of organ transplantation, “immunologic tolerance”, ie the maintenance of normal organ function without IS, has emerged as the ultimate treatment goal 3‐7 . The liver is well known as the most tolerogenic among transplantable organs, 8‐10 so the possibility of new clinical applications is most anticipated in this arena.…”

Section: Introductionmentioning

confidence: 99%

Clinical liver transplant tolerance: Recent topics

Takatsuki

Eguchi

2021

J Hepato Biliary Pancreat

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Background Immunosuppression is essential after organ transplantation to prevent severe graft injury due to rejection, but in long‐term, transplanted organs are generally accepted with minimal dose of immunosuppression, and adverse effects of it such as renal dysfunction, diabetes and development of malignancies might become to exceed over the benefits in majority of the cases. Accordingly, to achieve the immunologic tolerance has been the ultimate goal in organ transplantation, and the liver has been well recognized as the tolerogenic organ compared to other organs. Methods We referred the reported studies showing the actual protocol to achieve the immunologic tolerance after clinical liver transplantation. Results Actually, two main procedures as “elective weaning of immunosuppression” and/or “cell therapy” using various immune‐related cells have been introduced to induce the immunologic tolerance in clinical liver transplantation. The cell therapy, especially using regulatory T‐cell has been reported to achieve definitive immunologic tolerance in living donor liver transplantation. Conclusion Although it is still developing, the induction of immunologic tolerance in clinical liver transplantation is realistic. Herein, the current topics of immunologic tolerance in liver transplantation is described.

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Induction Phase of Spontaneous Liver Transplant Tolerance

Cited by 9 publications

References 77 publications

Transplant Tolerance, Not Only Clonal Deletion

Transplant Tolerance, Not Only Clonal Deletion

Dendritic Cell-Mediated Regulation of Liver Ischemia-Reperfusion Injury and Liver Transplant Rejection

Clinical liver transplant tolerance: Recent topics

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