Within the past decade, it has become apparent that the pathogenesis of IDDM is a progressive autoimmune destruction of pancreatic beta cells that precedes, by several years, the development of end organ failure. There exist two ways to deal clinically with IDDM. The first is to prevent the autoimmune destruction of the pancreatic beta cells prior to overt disease and the second is to attempt to replace beta cell function by beta cell transplantation or by hormone replacement (insulin). In this grant application, we propose to utilize allogeneic bone marrow hematopoietic stem cell isolation and transplantation into spontaneously autoimmune non- obese diabetic (NOD) mice in attempts to generate chimeric NOD mice that express both their own bone marrow elements and the additional bone marrow- derived cells from the allogeneic donor. Stem cell transplants differ from whole bone marrow grafts in that, although stem cells give rise to all hematolymphoid lineages, they are immature, """"""""uneducated"""""""" precursors of lymphoid cells and thus when transplanted do not elicit graft vs. host disease (GVHD). GVHD remains a major obstacle to the clinical use of bone marrow transplantation. This type of transplantation can serve two functions: First, successful stem cell engraftment might alter the recipient's immune system in such a way that the presence of the allogeneic lymphohematopoietic cells might confer protection against the host's own autoimmune response against islet beta cells. To test this, we plan to transplant NOD mice at a young age before they have developed massive beta cell destruction to determine if bone marrow chimerism will block the induction or perpetuation of insulitis and resultant hyperglycemia. Secondly, successful stem cell transplantation and resultant chimerism may alter the recipient's immune system's ability to respond against tissue from the donor. Thus, a chimeric NOD mouse may be able to accept islets, as well as other tissue transplants, from the donor strain of the hematopoietic stem cell transplant without the need for immunosuppression. The studies in this grant application propose a systematic approach to minimize immunosuppressive regimens and decrease morbidity associated with bone marrow transplantation as it specifically could apply to Type I diabetes. The ability to successfully transplant the hematopoietic cells of the bone marrow may provide a way to establish tolerance to islets from multiple donors without the need for long-term immunosuppression.
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