The acute rejection of allografts is mediated by alloantigen-specific T cells. Although the effector T cells are primed in the recipient lymphoid tissue, the factors directing the migration and infiltration of the primed T cells into the graft tissue remain unclear. An important parameter in facilitating leukocyte migration and infiltration into tissue is the presence of inflammation. Post-transplant inflammation, initially provoked by surgical trauma, is mediated through the production of proinflammatory cytokines and the induced expression of adhesion molecules on vascular endothelium. Recent results from this laboratory have indicated the amplified expression of genes encoding chemoattractant cytokines following transplantation of mice with allogeneic skin grafts when compared to the expression in control, syngeneic grafts. This amplified expression occurs prior to times post-transplant when primed alloantigen-specific T cells can be detected in the spleen or lymph nodes. On the basis of these results, we propose the hypothesis that the initial inflammatory response observed following transplantation is higher with increased immunogenetic disparity between the donor and recipient and that this amplified inflammatory response is mediated by innate cellular mechanisms following interaction of graft cells with infiltrating recipient cells. The experiments proposed in this application will test this hypothesis by determining the levels of inflammation in recipients transplanted with skin grafts of defined degrees of allogeneic difference, determining the sequential appearance of proinflammatory cytokine production during this initial inflammatory response, determining the interdependence of proinflammatory cytokine production, and determining the donor and recipient cellular components mediating the amplified inflammatory response following allogeneic skin transplantation. The results of these studies will address critical issues in the initiation of inflammation following transplantation of allogeneic grafts which facilitates the infiltration of effector T cells. The results should provide novel information, useful in the design or strategies to suppress or neutralize this initial inflammatory response and prolong the function and the survival of transplanted allografts.
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