This Program Project will address the mechanisms which produce altered host immunity and renal graft dysfunction in an experimental model of transplantation. Project Number 1 (Lipid Mediators in Renal Allograft Dysfunction, PI:Dr. P.Klotman) will evaluate the role of arachidonic acid metabolites as mediators of impaired excretory and hemodynamic function in rejecting allografts and during therapy with the immunosuppressive agent cyclosporine. Studies of the cellular source of these products combined with selective inhibition of the lipoxygenase and clyclooxygenase pathways will explore new modalities for the treatment and diagnosis of rejection and the prevention of cyclosporine toxicity. Project Number 2 (Effects of Host Immunity on Renal Allograft Function, PI:Dr. F.Sanfilippo) will examine the effects of host immune function on allograft function by evaluating factors such as presensitization immunogenetic disparity, and function on allograft function by evaluating factors such as presentation immunogenetic disparity, and pretransplant transfusions. Studies which correlate renal function with the morphologic appearance of specific T cell subsets will be combined with maneuvers which selectively deplete T helper and cytotoxic T cells in order to define the importance of these lymphocytes in producing impaired graft function. Project Number 3 (Role of Cytomegalovirus in Renal Transplantation, PI:Dr. J. Hamilton) will examine the renal cellular source of latent cytomegalovirus, the effects of latent and active cytomegalovirus infection on renal function, effects of virus-allograft interactions on immune function, the effects of cyclosporine on viral latency, and the role of virus in stimulating products of arachidonic acid metabolism. This program project should provide insight into the mechanisms of graft dysfunction with the goals of providing new therapeutic and diagnostic modalities for the management of rejection and its myriad complications.
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