To clarify the mechanism of chronicity and to explore therapeutic approach for viral hepatitis

直到现在，病毒性肝炎中的慢性肝炎的机制还不是很清楚。由于乙肝病毒(乙肝病毒)和丙型肝炎病毒(丙型肝炎病毒)不是细胞病变，因此认为乙肝病毒和丙型肝炎病毒感染时的肝损伤是由宿主免疫反应攻击病毒感染的肝细胞引起的。并模糊地认为对病毒蛋白的免疫反应薄弱是病毒性肝炎慢性化的原因。为了阐明慢性化的机制，对宿主免疫反应的主要效应者之一的细胞毒性T淋巴细胞(CIL)的功能进行了体外研究。在无共刺激信号存在的情况下，CIL的增殖活性和杀伤活性在抗原刺激后明显受损。提示缺乏共刺激分子表达的肝细胞在接触后可使CILs失活，这可能是肝炎病毒持续存在的主要机制之一。乙肝病毒转基因小鼠(TG)是人类携带乙肝病毒的动物模型。HBs-cDNAs-Tg免疫在一定程度上下调了病毒的表达，但病毒产物被完全清除的情况非常少见。为了提高病毒下调的效果，同时用HBs的cDNA和共刺激分子(B7 1、B7 2或CD40)免疫HBVTG。尽管两种分子联合免疫并不能增加病毒在HBs-TG中的完全下调比例，但它导致了单独免疫HBs-cDNA时没有观察到的肝炎的表现。提示联合免疫可提高诱导乙肝病毒特异性免疫应答的效果。同时使用共刺激分子进行免疫，可能是治疗慢性肝炎病毒感染的方法的线索。

The mechanism of chtonicity in viral hepatitis is not well understood until present. Since hepatitis B virus (HBV) and hepatitis C virus (HCV) are not cytopathic, hepatic injury in HBV and HCV infection is thought to be caused by the attack of host immune responses against virus-infected hepatocytes. And it is vaguely thought that the weakness of the immune responses against viral proteins is responsible for the chronicity of viral hepatitis. To elucidate the mechanism of the chronicity, the functions of the cytotoxic T lymphocyte (CIL), one of the main effectors of host immune responses is studied in vitro. The functions of CIL, both proliferative activity and the killing activity were greatly impaired after antigen stimulation without the existence of costimulatory signals. This implies that the hepatocytes lacking the expression of costimulatory molecules may inactivate the CILs after contact and that it may be one of the main mechanisms for the persistence of hepatitis viruses. HBV-transgenic mice (Tg) are the models for HBV carriers in human. Immunization of HBV-Tg with HBs-cDNA results in the downregulation of the virus to some extent, however, the occurrence of complete clearance of viral products is very rare. To increase the efficacy of viral downregulation , cDNAs of HBs and costimulatory molecules (B7 1, B7-2, or CD40) were simultaneously used to immunize HBV-Tg. Although co-immunization with both molecules did not increase the ratio of complete viral downregulation in HBV-Tg, it resulted in the manifestation of hepatitis that was not observed in the immunization of HBs-cDNA alone. This suggests that the efficacy of inducing HBV-specific immune response is improved by the co-immunization. Simultaneous use of costimulatory molecules for immunization may be the clue for the thrapeutic approach to treat chronic infection of hepatitis viruses.