Successful Tolerance to Fully MHC Disparate Renal Allografts via Donor Hematopoietic Mixed Chimerism in Non-Human Primates

Bénichou, Gilles; Nadazdin, O.; Cosimi, A. Benedict; Kawai, Tatsuo

doi:10.1111/ajt.12366

Cited by 6 publications

(3 citation statements)

References 5 publications

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“…The association of chimerism with immunological tolerance emerged from the work of Owen and Billingham on Freemartin cattle . Since that first report, mixed chimerism induced in adults with pre‐existing immune systems has been shown to induce T‐ and B‐cell tolerance across allogeneic barriers in rodents , large animals , and humans . We have also extensively studied the strategy of inducing mixed chimerism for tolerance induction across the xenogeneic barrier.…”

Section: Mixed Chimerism For T‐ and B‐cell Tolerancementioning

confidence: 99%

Xenotransplantation: immunological hurdles and progress toward tolerance

Griesemer

Yamada

Sykes

2014

Immunological Reviews

134

107

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The discrepancy between organ need and organ availability represents one of the major limitations in the field of transplantation. One possible solution to this problem is xenotransplantation. Research in this field has identified several obstacles that have so far prevented the successful development of clinical xenotransplantation protocols. The main immunologic barriers include strong T cell and B cell responses to solid organ and cellular xenografts. Additionally, components of the innate immune system can mediate xenograft rejection. Here, we review these immunologic and physiologic barriers and describe some of the strategies that we and others have developed to overcome them. We also describe the development of two strategies to induce tolerance across the xenogeneic barrier, namely thymus transplantation and mixed chimerism, from their inception in rodent models through their current progress in pre-clinical large animal models. We believe that the addition of further beneficial transgenes to Gal knockout swine, combined with new therapies such as Treg administration, will allow for successful clinical application of xenotransplantation.

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Section: Mixed Chimerism For T‐ and B‐cell Tolerancementioning

confidence: 99%

Xenotransplantation: immunological hurdles and progress toward tolerance

Griesemer

Yamada

Sykes

2014

Immunological Reviews

134

107

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“…The MGH regimen consisted of low dose total body and local thymic irradiation, horse anti-thymocyte globulin (ATG), a cosimulatory blockade (either by anti-CD154 mAb or belatacept), and a weak course of cyclosporine (CyA). Although the reason for the disparate outcomes between the Emory and the MGH studies remains to be clarified [71], absence of lymphoid chimerism in recipients of the Emory regimen may be a key factor in the failure of renal allograft tolerance, since previous studies at MGH showed that induction of lymphoid chimerism was correlated with long-term allograft survival [63]. …”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell infusion/transplantation for induction of allograft tolerance

Granados

Bénichou

Kawai

2015

Current Opinion in Organ Transplantation

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Purpose of review This review updates the current status of basic, preclinical, and clinical research on donor hematopoietic stem cell infusion for allograft tolerance induction. Recent findings Recent basic studies in mice provide evidence of significant involvement of both central deletional and peripheral regulatory mechanisms in induction and maintenance of allograft tolerance effected through a mixed chimerism approach with donor hematopoietic stem cell infusion. The presence of heterologous memory T cells in primates hampers the induction of persistent chimerism. Durable mixed chimerism, however, now has been recently induced in inbred major histocompatibility complex-mismatched swine, resulting in tolerance of vascularized composite tissue allografts. In clinical transplantation, allograft tolerance has been achieved in human leukocyte antigen-mismatched kidney transplantation after the induction of transient mixed chimerism or persistent full donor chimerism. Summary Tolerance induction in clinical kidney transplantation has been achieved by donor hematopoietic stem cell infusion. Improving the consistency and safety of tolerance induction and extending successful protocols to other organs, as well as to organs from deceased donors, are critical next steps to bringing tolerance to a wider range of clinical applications.

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“…At this time point, the mixed chimerism-conditioning regimen is initiated and the donor bone marrow given [12]. This approach has been successful in inducing tolerance for MHC-mismatched renal [23] and lung [24 && ] allografts. In the lung study, three of four nonhuman primates became tolerant of their allografts, with two of three tolerant animals exhibiting stable mixed chimerism and the third tolerant animal demonstrating transient chimerism but remaining tolerant of the lung allograft.…”

Section: Extension Of Tolerance Protocols To Fullmismatches and Deceamentioning

confidence: 99%

Tolerance induction via mixed chimerism in vascularized composite allotransplantation

Cetrulo

Drijkoningen

Sachs

2015

Current Opinion in Organ Transplantation

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Induction of tolerance in renal allograft transplantation has been achieved clinically, via mixed chimerism protocols. Modifications of these protocols for transplants, which require use of deceased donors across full MHC mismatches, have shown promise in preclinical models. It is therefore appropriate to consider evaluation of these protocols in clinical trials for kidney transplants, and if successful, for VCA.

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Successful Tolerance to Fully MHC Disparate Renal Allografts via Donor Hematopoietic Mixed Chimerism in Non-Human Primates

Cited by 6 publications

References 5 publications

Xenotransplantation: immunological hurdles and progress toward tolerance

Xenotransplantation: immunological hurdles and progress toward tolerance

Hematopoietic stem cell infusion/transplantation for induction of allograft tolerance

Tolerance induction via mixed chimerism in vascularized composite allotransplantation

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