In spite of the development of new immunosuppressive drugs, chronic and acute rejection remains a significant cause of patient morbidity, organ failure, and death in human solid organ transplantation. The goal of this project is to determine whether injection of donor stem cells into the thymus can result in (1) stem cell engraftment and persistent peripheral blood microchimerism (coexistence of donor cells in recipient blood without inducing a recipient immune attack) and (2) modification of the recipient's immune system and prolonged graft survival of solid organ grafts from the stem cell donor. The ultimate objective of these studies is to develop a method of inducing tolerance (acceptance) of a solid organ graft without the use of life-long immunosuppressive drugs. In previous years we showed that intrathymic stem cell implantation could result in long-term survival of donor-derived cells and that this resulted in prolonged skin graft acceptance. We are currently evaluating the characteristics of various sub-types of bone marrow stem cells to determine which populations are """"""""best"""""""" for intrathymic transplantation and achieving microchimerism. This is being done by (1) in vitro assays evaluating stem cell sub-types by cell surface markers and functional characteristics and (2) in vivo experiments, transplanting different populations of stem cells into experimental animals and monitoring development of microchimerism. Results obtained during the past year suggest that bone marrow-derived stem cells are very heterogeneous, and that the specific type of cell used for intrathymic transplantation may be critical to the success of this method of modifying the recipient immune system. Future studies will evaluate the effects of stem cell transplantation and microchimerism on the acceptance of a solid organ (heart) graft. These studies are being performed in primates because these animals provide the most direct model for refining this method before it is tested in transplant patients.
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