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

病毒性肝炎中压性的机制目前还不清楚。由于乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）不会引起细胞病变，因此HBV和HCV感染的肝损伤被认为是由宿主免疫应答对病毒感染的肝细胞的攻击引起的。人们模糊地认为，对病毒蛋白免疫反应的薄弱是病毒性肝炎的慢性原因。为了阐明其慢性机制，我们在体外研究了宿主免疫应答的主要效应器之一细胞毒性T淋巴细胞（CIL）的功能。在没有共刺激信号存在的情况下，CIL的功能，无论是增殖活性还是杀伤活性都受到了极大的损害。这表明缺乏共刺激分子表达的肝细胞可能在接触后使CILs失活，这可能是肝炎病毒持续存在的主要机制之一。HBV转基因小鼠（Tg）是人类HBV携带者的模型。用HBs-cDNA免疫HBV-Tg可在一定程度上导致病毒的下调，但病毒产物完全被清除的情况非常罕见。为了提高病毒下调的效果，HBs和共刺激分子（B7 1、B7-2或CD40）的cdna同时用于免疫HBV-Tg。虽然这两种分子的联合免疫并没有增加HBV-Tg中病毒完全下调的比例，但它导致了单独免疫hbv - cdna时没有观察到的肝炎表现。提示联合免疫可提高诱导hbv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治疗方法的线索。

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.