A serine protease inhibitor, N-alpha-tosyl-L-lysine chloromethyl ketone, prolongs rat hepatic allograft survival

Background. Serine protease inhibitors have profound suppressive effects on cellular and humoral immune responses. We investigated the effect of a ser ine protease inhibitor, N-alpha -tosyl-L-lysine chloromethyl ketone (TLCK), on hepatic allograft survival in rats. Methods. Orthotopic hepatic transpl antation was performed in an ACI (RT1(a))-to-LEW (RT1(1)) rat combination. TLCK was administered continuously at a dose of 4.4 mg/kg/day using an osmo tic subcutaneous infusion minipump. Results. TLCK prolonged hepatic allograft survival. Histologic staging of a cute rejection based on Banff criteria in TLCK-treated hepatic allografts w as significantly lower than in untreated allografts. TLCK significantly red uced serum concentrations of interferon (IFN)-gamma and tumor necrosis fact or (TNF) a in allograft recipients. TNF-alpha mRNA levels in TLCK-treated a llografts were significantly lower than in untreated allografts. TLCK also decreased perforin mRNA levels in hepatic allografts. Hepatic infiltrates e luted from TLCK-treated allografts showed significantly lower cell-mediated lympholytic activity against donor Con A blast cervical lymph node cells t han those from untreated allografts. In vitro, TLCK suppressed interleukin- 2 production and [H-3]thymidine incorporation into an allogeneic mixed lymp hocyte reaction. Conclusion. TLCK suppressed acute allograft rejection, suggesting a novel i mmunosuppressive strategy for therapy of acute organ rejection. (C) 2001 Ac ademic Press.