Association of chronic thromboxane inhibition with reduced in situ cytotoxic T cell activity in rejecting rat renal allografts.
The development of allospecific cellular immunity during acute rat renal allograft rejection parallels alterations occurring in arachidonic acid metabolism, including increased production of the vasoconstrictor eicosanoid thromboxane A2 (TxA2). We have previously demonstrated that chronic inhibition of thromboxane synthetase is associated with improved renal allograft function as well as significant reductions in renal production and urinary excretion of Tx metabolites. In this study, we evaluated the effects of chronic administration of the specific Tx synthetase inhibitor OKY-046 on in situ and systemic alloimmune effector cell function. PVG (RT1c) strain rats were transplanted with fully allogeneic ACI(RT1a) kidneys, and intrarenal artery infusion of OKY-046 (50 micrograms/mg/min) or its saline vehicle was begun at the time of surgery utilizing an osmotic pump. Four days following transplantation, spleen cells and inflammatory cells eluted from the graft were tested. The frequency of antidonor precursor cytotoxic T cells (pCTL), as measured by limiting dilution assay, was consistently lower in allografts from OKY-046-treated animals (1/3146-1/5160) compared with vehicle treatment (1/661-1/1878), while no difference in pCTL ranges were seen in splenocytes from both groups. However, following short-term culture (10-15 days, lymphocytes from treated and control allografts were equally proficient in specifically lysing donor targets. Proliferative response to donor stimulators measured by mixed lymphocyte reaction assays were consistently greater in spleen cells than allograft eluate cells for both groups, but there were no significant differences between OKY and vehicle groups in terms of either splenocyte or allograft eluate proliferative responses. Immunohistologic labeling and flow cytometric analysis of renal allograft infiltrates showed similar percentages and distributions of immune cell populations in treated and control groups. These results suggest that Tx inhibition is capable of temporarily reducing cytotoxic T cell function in the local environment, which may partially account for the improved graft function seen.
Ruiz, P; Coffman, TM; Klotman, PE; Sanfilippo, F
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