This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Transplantation has emerged as the preferred method of treatment for many forms of end-stage organ failure. The development of strategies to promote the acceptance of allogeneic tissues without the need for chronic immunosupression could reduce the risk of life-threatening complications and expand the application of organ transplantation for other diseases.In the past year, we made significant progress towards the development of novel non-myeloablative protocols using CD28 and CD40/CD154 T cell costimulation-blockade-based therapeutics to permit the induction of high levels of hematopoietic chimerism in Rhesus macaques. We undertook a pedigree and MHC analysis of the Yerkes colony which has allowed us, in the past year, to perform the first bone marrow transplants between rhesus macaque donors and recipients with known familial relationships and MHC similarity. Our data suggest that in the setting of increased MHC matching Sbetween transplant donors and recipients, costimulation blockade-based induction of durable chimerism and resultant tolerance to solid organ transplants is achievable, with preservation of protective immunity. During the reporting period we developed a regimen that represents the first successful, reproducible strategy for induction of macrochimerism in a non-human primate model. We led a multi-center effort to determine the degree of family relatedness and the degree of MHC matching in a cohort of Rhesus macaques and changed the way hematopoietic stem cell transplants are performed and analyzed in the Rhesus model.We also performed the first nonmyeloablative bone marrow transplant in a Rhesus macaque between a donor and recipient who are full siblings and are MHC matched. Additionally, we established macrochimerism for the first time using a nonmyeloablative conditioning regimen and hematopoietic stem cells derived from mobilized peripheral blood. This advance allows us to perform stem cell transplantation from living donors, which will facilitate post-transplant immune monitoring.
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