Biobreeding (BB) rats spontaneously develop insulin dependent type I diabetes. T cells from BB rats proliferate poorly in response to alloantigen in vitro when compared to non diabetes prone, normal rats. That this proliferative dysfunction may be causal for diabetes is suggested by the observation that animals protected from disease by neonatal inoculation with bone marrow from non diabetes prone adult donors also have normal T cell function. Removal of the mature T cell subset eliminates the protective effect of the bone marrow suggesting that T cell precursors from normal donors fail to mature properly in the diabetes prone environment. The preliminary results in this proposal identify the thymus as a crucial site in defining the diabetes prone environment. BB rats which were adult thymectomized(at), lethally irradiated(x) and reconstituted with T cell depleted syngeneic bone marrow(bm), termed BBatxbm, lack demonstrable T cell mediated responses. The transplant of a DA/BB F1 thymus graft (DA is allogeneic and incompatible with BB at the major histocomptibilty complex. The DA/BB F1 is not diabetes prone and has no obvious T cell dysfunction) resulted in restoration of the proliferative and cytotoxic responses to levels observed with normal F1 rats. Conversely, T cells from DA/BB atxbm transplanted with BB thymus grafts proliferated poorly in the range observed for normal BB rats. With increasing time post thymus transplant T cells from DA/BB atxbm + BB thymus exhibited a return to normal proliferative responses. We hypothesized that this result was due to the repopulation of the BB thymus with F1 marrow derived cells. When the thymus tissue was treated with 2 deoxyguanosine (2dGua) prior to transplant the results were different. (2dGua is toxic for marrow derived resident macrophage/dendritic cells and thymocytes but spares the thymic epithelium) T cells from BBatxbm +DA/BB2dGua thymus expressed the T cell proliferative dysfunction while BB/DAatxbm +BB2dGua T cells did not. WE interpret these results to suggest that a population of cells of bone marrow origin (not a thymocyte and most likely a cell of the macrophage/dendritic cell lineage) which resides in the thymus is highly influential in determining the functional characteristics of the mature T cells which have matured in that thymic environment. These results, if confirmed, provide and explanation for the published studies concluding that the T cell defect maps to the marrow rather than the thymus. It should also be possible to determine if reversal of the T cell dysfunction results in any protective influence from the development of diabetes.
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