Renal allografts undergoing acute rejection demonstrate augmented metabolism of arachidonic acid (AA) to form a variety of cyclooxygenase (CO) and lipoxygenase (LO) products. These products of AA metabolism, or eicosanoids, exert powerful effects on net renal function as well as directly on the immune system (initial pilot studies in the mouse model). This proposal investigates the role of altered eicosanoid production on immune cell function during renal allograft rejection in the rat model with the specific aim that a novel form of controlled immunosuppression can be achieved. Additionally, a new concept is proposed whereby an efficient means of mesangial dendritic cell depletion from donor renal tissue can be accomplished via pharmacologic manipulation a AA metabolism prior to allotransplantation. The relationship between localization of these resident leukocytes and eicosanoid production has been demonstrated but remains incompletely understood. The effects of alterations in AA metabolism directly upon immune active cells in the rat spleen will initially be studied by lectin proliferation assays, cell mediated cytotoxicity assays, mixed lymphocyte reactions, and interleukin-2 production. Using a rat renal allograft mode, similar immunologic studies as well as subset analysis of graft infiltrating cells will be performed. Qualitative and quantitative changes in AA metabolism will be monitored by RP-HPLC profiles of radiolabeled products derived from 3H-AA substrate and radioimmunoassay, respectively. The strategy will be to inhibit """"""""pro-rejection"""""""" eicosanoids (TXA2, LO products) and enhance """"""""anti-rejection"""""""" eicosanoids PGI2, PGE2) by administering compounds which alter AA metabolism either alone or in combination. It is hypothesized that controlled alterations in AA metabolism can yield a controlled downregulation of the rejection response with improvement in allograft survival. Correlations of alterations in immune cell function through manipulations in eicosanoid production may enhance our understanding of mechanisms involved in acute rejection. Through this unique model of altered AA metabolism, the role of donor tissue dendritic cells can also be assessed.
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