T-CELL-MEDIATED AUTOLOGOUS HEPATOCYTOTOXICITY IN PATIENTS WITH CHRONIC HEPATITIS-C VIRUS-INFECTION

Virus-specific cytotoxic T lymphocytes (CTLs) have been suggested to b e responsible for the liver injuries in patients with hepatitis C viru s (HCV) infection. However, there has been no report of direct evidenc e to substantiate this hypothesis. In this study, we performed in vitr o autologous hepatocytotoxicity assay in 45 patients to examine a poss ible role of CTLs to HCV-infected liver cells. The data were correlate d with histology activity index of liver biopsy specimens. Lymphocyte subsets and hepatocyte expression of human major histocompatibility co mplex antigens class I and class II (HLA-I and HLA-H) were also evalua ted. The immunohistochemical study showed more prominent HLA-I express ion than HLA-II on hepatocytes (mean score +/- SEM: 2.34 +/- 0.11 vs. 0.42 +/- 0,08; P < .01). The lymphocyte subset analysis showed that CD 8+ T cells were dominant in the lobular areas showing spotty necrosis, whereas CD4+ T cells were prominent in the portal and periportal area s CP < .01). Most patients had a significant T cell-mediated cytotoxic ity to hepatocytes as compared with non-T cells (percentage cytotoxici ty +/- SEM: 46.4 +/- 2.3 vs. 13.8 +/- 2.7; P < .001). T cell-mediated hepatocytotoxicity had a linear correlation with HAI CP < .05). The T cell-mediated cytotoxicity could be blocked by anti-CD8 (43.7% vs. 9.5 %, P < .05) or by anti-HLA-I (43.7% vs. 18.5% P < .05) but not by anti -CD4 or anti-HLA-II monoclonal antibodies. These findings strongly sug gest that HLA-I-restricted, CD8+ T cell-mediated hepatocytotoxicity is an important pathogenetic mechanism in patients with chronic HCV infe ction.