Abstract
The definition of immune tolerance to allogeneic tissue and organ transplants in laboratory animals and humans continues to be the acceptance of the donor graft, rejection of third-party grafts, and specific unresponsiveness of recipient immune cells to the donor alloantigens in the absence of immunosuppressive treatments. Actively acquired tolerance was achieved in mice more than 60 years ago by the establishment of mixed chimerism in neonatal mice. Once established, mixed chimerism was self-perpetuating and allowed for acceptance of tissue transplants in adults. Successful establishment of tolerance in humans has now been reported in several clinical trials based on the development of chimerism after combined transplantation of hematopoietic cells and an organ from the same donor. This review examines the mechanisms of organ graft acceptance after establishment of mixed chimerism (allo-tolerance) or complete chimerism (self-tolerance), and compares the development of graft versus host disease (GVHD) and graft versus tumor (GVT) activity in complete and mixed chimerism. GVHD, GVT activity, and complete chimerism are also discussed in the context of bone marrow transplantation to treat hematologic malignancies. The roles of transient versus persistent mixed chimerism in the induction and maintenance of tolerance and organ graft acceptance in animal models and clinical studies are compared. Key differences in the stability of mixed chimeras and tolerance induction in MHC matched and mismatched rodents, large laboratory animals, and humans are examined to provide insights into the safety and efficacy of translation of results of animal models to clinical trials.
Highlights
About 500,000 patients with end stage renal disease are undergoing dialysis in the US of which over 100,000 are on a wait list for a deceased or living donor transplants [1]
***Grade 4 neutropenia ***Grade 4 thrombocytopenia ***Grade 3 Anemia ICU stay during 1st 90 days Chimerism goal GVHD risk GVHD related death **** Apparent need for medical teams to support post-transplant care beyond SoC renal transplant team Ability to directly translate to recipients of deceased donor transplants
The rodent models summarized in this review uniformly demonstrated that mixed chimerism and tolerance were stable after MHC matched and mismatched combined hematopoietic progenitor and organ transplantation [38, 39, 44,45,46,47,48,49,50,51,52]
Summary
About 500,000 patients with end stage renal disease are undergoing dialysis in the US of which over 100,000 are on a wait list for a deceased or living donor transplants [1]. This review will concentrate on preclinical models of chimerismbased transplantation tolerance, and highlight the bench-tobedside adaptation of the models by combining living donor kidney and hematopoietic cell transplantation to purposefully withdraw IS medications from patients while maintaining normal graft function. Reports of cancer patients with complete chimerism after bone marrow transplantation and who thereafter developed end stage renal disease (ESRD) accepted a kidney transplant from their bone marrow donor, and without the need for immunosuppressive (IS) drugs [29, 30]. Complete chimeras can develop donor immune cells that are unresponsive to recipient alloantigens [31, 32] This represents graft versus host (GvH) acceptance. The use of pretransplant host conditioning using total lymphoid irradiation (TLI) combined with anti-thymocyte globulin (ATG) or the administration of cyclophosphamide shortly after bone marrow transplantation in laboratory animals and in humans has been shown to establish GvH acceptance that prevents GVHD [27, 32, 33]
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