Inbred rat and outbred canine models will be used to develop strategies that can elevate clinical intestinal and multivisceral transplant procedures from their present state of excessive morbidity and mortality to more safe and cost effective operations. The protocols are based on the discovery that passenger leukocytes of bone marrow in all organs migrate after transplantation and produce persistent chimerism, evidence suggests that this is essential for sustained survival of the grafts. However, intestinal passenger leukocytes have inferior tolerogenic qualities compared to bone marrow, and in addition have a lineage profile that predisposes to graft versus host disease (GVHD). This donor leukocyte population will be modified by irradiation of the intestinal and multivisceral organs at doses that are non-injurious to the epithelial/vascular components, with or without adjunct donor bone marrow. The end points will be quantity and quality of the post-transplant chimerism, weight, development, and survival of the recipients; clinical and histopathologic evidence of rejection and/or GVHD; and outcome after discontinuance of immunosuppression. Variables in the basic control and experimental groups will be: (a) the doses of irradiation and/or adjunct bone marrow, (b) recipient treatment with hematolymphopoietic growth factors, (c) alternative (to irradiation) methods of intestinal passenger leukocyte lineage depletion. The project calls for initial emphasis on inbred rat strain combinations in which rejection and GVHD can be delineated separately. These experiments are expected to elucidate more clearly the mechanisms of graft acceptance as these apply to all organs. Based on the results, work will proceed to the clinically more relevant outbred canine models.
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