Involvement of the Fas system in liver allograft rejection

OBJECTIVE: Recent studies suggest that apoptosis is an important mechanism of cell death in the rejection of liver allografts and that this process is mediated via Fas. The aim of this study was to analyze the expression of the Fas system during the liver allograft rejection and its evolution after treatment. METHODS: We evaluated 14 patients with liver allograft rejection before and after treatment. Fas immunostaining, was performed by the labeled streptavidin-biotin peroxidase method using a 200-fold dilution of a monoclonal antibody. Assessment of apoptosis was determined by the terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) technique on deparaffined liver samples. Serum levels of soluble Fas antigen (sFas) were detected by an enzyme immunoassay procedure. Twelve liver transplant patients without allograft rejection were analyzed as a control group. RESULTS: The number of hepatocytes expressing Fas antigen, the percentage of apoptotic hepatocytes, and the sFas levels were higher in patients with liver allograft rejection than in controls (27.9 +/- 23. 1 % vs 1.4 +/- 1.2%, p < 0.001; 2.2 +/- 0.9% vs 1.0 +/- 0.1%, p = 0.02; 24.2 +/- 39.6 vs 2.8 +/- 4.0 IU/ml, p = 0.03, respectively). There was a correlation between the levels of sFas, AST (r = 0.86, p < 0.001), ALT (r = 0.78, p = 0.02), and gamma-globulin levels (r = 0.86, p < 0.001). After the rejection treatment we found a significant decrease in the Fas antigen expression (18.6 +/- 13.3 %, p < 0.05), TUNEL index (0.2 +/- 0.4, p < 0.05), and levels of sFas (9.9 +/- 30.25 IU/ml, p = 0.005). CONCLUSIONS: 1) The demonstration of hepatocytes with Fas antigen expression and the labeling of the nuclei by the TUNEL assay suggest that apoptosis mediated by the Fas system plays a role in the pathogenesis of liver allograft rejection. 2) The Fas expression and the sFas levels decreased in patients with treatment response.