Therapeutic approach to hepatitis C by regulation of apoptosis-related gene

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Cytotoxic T lymphocytes (CTL) play an important role in liver cell injury by hepatitis C virus (HCV) infection. We demonstrated that liver-infiltrating CD8 positive lymphocytes and natural killer cells expressed the functional Fas ligand. On the other hand, B7/BB-1 was strongly expressed in the cytoplasm of hepatocytes of HCV-infected liver. B7/BB-1-positive cells accompanied liver-infiltrating lymphocytes and were detected near HCV core antigen-and HLA class I-positive cells. B7/BB-1 expression was closely correlated with the activity of viral hepatitis. These findings suggest that B7/BB-1 expression by hepatocytes may be induced by HCV infection and may trigger generation and activation of CTL,which may cause damage to HCV-infected HLA class I-expressing hepatocytes via Fas antigen.We measured the serum level of soluble Fas antigen (sFas) in patients with chronic hepatitis C and healthy volunteers. The serum sFas level was significantly higher in chronic hepatitis C patients than in … More healthy volunteers. It was also correlated with the expression level of Fas in hepatocytes and the severity of liver inflammation. Thus it may serve as a novel indicator for the activity of liver inflammation.When HLA typing was tested among HCV-infected individuals, extended haplotypes including class I B54 are closely associated with the progression of liver injury, whereas extended haplotypes including class II DRB1^*1302-DQB1^*0604 are associated with low hepatitis activity. Thus the host factors as well as viral factors may determine the activity of CTL.We showed that endogeneous TGF-beta1 block the induction of HCV-specific CTL and their cytolytic activity. By exvivo cell system, we demonstrated that the appropriate does of IL-2 and addition of anti-TGF-beta1 can induce the high cytotoxicity of CTL.The high activity was also introduced by using dendritic cells as antigen-presenting cells.In summary, cytotoxic activity of CTL via Fas system plays a dominat role in liver cell damage by HCV infection. Some cytokines such as TGF-beta1 can modulate the CTL activity and regulate liver apoptosis. Less