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

细胞毒性T淋巴细胞（CTL）在丙型肝炎病毒（HCV）感染引起的肝细胞损伤中起重要作用。我们证明了肝脏浸润的CD 8阳性淋巴细胞和自然杀伤细胞表达功能性Fas配体。另一方面，B7/BB-1在HCV感染的肝细胞的细胞质中强烈表达。B7/BB-1阳性细胞伴随肝脏浸润淋巴细胞，并在HCV核心抗原和HLA I类阳性细胞附近检测到。B7/BB-1表达与病毒性肝炎活动性密切相关。这些结果表明，B7/BB-1的肝细胞表达可能是由HCV感染诱导，并可能触发CTL的产生和激活，这可能会造成损害，HCV感染的HLA-I类表达的肝细胞通过Fas抗原。慢性丙型肝炎患者血清sFas水平显著高于慢性乙型肝炎患者， ...更多信息 健康志愿者肝细胞Fas表达水平与肝脏炎症程度相关。当在HCV感染者中进行HLA分型时，包括I类B54在内的扩展单倍型与肝损伤的进展密切相关，而包括II类DRB 1 ^*1302-DQB 1 ^*0604在内的扩展单倍型与低肝炎活动性相关。因此，宿主因素以及病毒因素可能决定CTL的活性。我们发现，内源性TGF-β 1阻断HCV特异性CTL的诱导及其细胞溶解活性。通过体外细胞系统，我们证实了适当剂量的IL-2和抗TGF-β 1抗体的加入可以诱导CTL产生高的细胞毒活性，并利用树突状细胞作为抗原提呈细胞，诱导CTL产生高的细胞毒活性，说明CTL通过Fas系统的细胞毒活性在HCV感染肝细胞损伤中起主导作用。一些细胞因子如TGF-β 1可以调节CTL活性，调节肝细胞凋亡。少

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