Analysis of the mechanism of liver damage and carcinogenesis in patients with chronic hepatitis C virus infection.

在丙型肝炎病毒感染的肝脏中，B7/BB-1在肝细胞胞浆中呈强阳性表达。B7/BB-1阳性细胞伴随肝脏浸润性淋巴细胞，分布于HCV核心抗原和HLAI类阳性细胞附近。B7/BB-1的表达与病毒性肝炎活动性密切相关。这些结果提示，肝细胞表达B7/BB-1可能是由丙型肝炎病毒感染诱导的，并可能触发CTL的产生和激活，从而可能对表达丙型肝炎病毒感染的人类白细胞抗原I类的肝细胞造成损害。为探讨肝细胞癌发生的危险因素及干扰素治疗后肝细胞癌的发生率，对1022例接受干扰素治疗的慢性丙型肝炎患者进行了13~97个月的超声随访。瞬时应答者肝细胞癌的累积发生率与持续应答者几乎相同，无应答者显著高于持续应答者和瞬时应答者。The…持续应答者、暂时性应答者和无应答者的肝细胞癌7年以上累积发病率估计分别为4.3%、4.7%和26.1%。COX回归分析显示，干扰素治疗后肝细胞癌高危组患者多为无反应、年龄大、男性。针对丙型肝炎病毒RNA的锤头状核酶切割靶病毒RNA，对病毒翻译有明显的抑制作用，提示核酶介导的丙型肝炎病毒RNA切割可能成为治疗丙型肝炎病毒感染的新策略。与未转染人B7-1的肝癌细胞相比，转染人B7-1的人肝癌细胞在体外具有较强的细胞杀伤活性，提示B7-1高表达的人肝癌细胞可用于诱导抗人肝癌免疫反应。与野生型肝癌细胞相比，B7-1转基因肝癌细胞在同基因BALB/c小鼠体内的肿瘤生长受到明显抑制，提示B7-1转基因肝癌细胞在体内诱导了抗肿瘤免疫。因此，将B7-1基因转移到肝癌细胞中可能是人类肝癌基因治疗的候选方法之一。这些发现可能有助于阐明肝损伤的机制，提高治疗慢性丙型肝炎患者的疗效。较少

In hepatitis C virus (HCV)-infected liver, B7/BB-1 was strongly expressed in the cytoplasm of hepatocytes. 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. To elucidate the risk factors for liver carcinogenesis and to examine the incidence of hepatocellular carcinoma (HCC) after interferon therapy, 1022 chronic hepatitis C patients treated with interferon were followed by ultrasonography for 13-97 months. The cumulative incidence of HCC in transient responders was almost equal to that in sustained responders, and it was significantly higher in non-responders than in sustained and transient responders. The … More seventh-year cumulative incidence rates of HCC in sustained responders, transient responders and non-responders were estimated to be 4.3%, 4.7% and 26.1%, respectively. Cox regression analysis showed that patients in the high risk gropu of HCC after interferon therapy were those showing no response, who were older and who were male.The hammer-head ribozymes directed against HCV RNA cleaved the target HCV RNA and showed a significant inhibitory effect on viral translation, suggesting that ribozyme-mediated HCV RNA cleavage may serve as a new strategy in the treatment of HCV infection. Human B7-1 transfected HCC 'Is could induce cytolitic activity in vitro compared with B7-1 non-transfected HCC cells, suggesting that human HCC cells with strong expression of B7-1 by ex vivo or in vivo transfection could be used to induce antitumor immunity against human HCC.Tumor growth of B7-1 transfected HCC cells in syngenetic BALB/c nu/nu mouse was as fast as that of wild HCC cells. However, tumor growth of B7-1 transfected HCC cells in syngenetic BALB/c mouse was significantly inhibited compared with that of wild HCC cells, suggesting that antitumor immunity against HCC cells was induced by B7-1 transfected HCC cells in vivo. Thus, B7-1 gene transfer into HCC cells may be one of the candidates for human HCC gene therapy.These findings may lead to clarify the mechanism of liver damage and to improve the efficacy of the treatment for patients with chronic HCV infection. Less