Development of molecular and diagnostic of acute rejection after organ transplantation

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The acute rejection in organ transplantation lias been shown to be mediated by cytotoxic T lymphocytes (CTL) and lots of evidences revealed that the effectors molecules such as serine protease (SE) or perforin contained in graiitiles of CTL are related to the process of cell killing against the target cells. The aim of this study is to investigate the whether these new findings are useful for diagnosis and immunosuppressive therapy in organ transplantation. SE activity was measured by cleaving of the esterase substrate N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester (BLT). First we investigated whether SE activity assay could serve as a sensitive tool for monitering of acute rejection. The rapie increase in SE activily of peripheral blood lymphocytes (PBL) and graft infiltrating lymphocytes (GIL) according to progress of rejection was observed on and after the day 6 in non-treatment group in contrast with the changeless activity in cyclospolin group. Second, we live purified perforin inhibitor protein (P-1) from rat serum using serial column chromatographic steps. P-1 inhibited in a dose dependent manner the cytotoxic activity of cytotoxic T lympliocytes (CTL). LEW rat recipients receiving only a BN renal allografts survived for a mean survival time of 7.9 days (control : group A). Each group of recipients receiving P-1 of 2mg/kg/day (grotip B) or 4mg/kg/day (group C) for 7 days posttransplant showed extensive prolongation of survival in a dose dependent manner (group B : 14.5 days ; group C : 22.9 days). It is concluded that the P-1 could serve as a novel immunosuppressive agent and us one of the clue to resolve the actual roles of perforin in effector mechanisms.