IMMUNO-PATHOGENESIS AND-THERAPY OF VIRAL HEPATITIS

用B肝炎病毒（HBV）转基因小鼠（TgM）研究病毒性肝炎的免疫发病机制。通过检测血清ALT水平监测HBV TgM过继转移HBV特异性细胞毒性T淋巴细胞（CTL）后的肝损伤情况，并通过检测转移后第5天TgM肝脏中HBV mRNA的残留量监测CTL的抗病毒作用，分析不同特异性、不同TCR和不同细胞因子谱的CTL对疾病严重程度和病毒清除的影响。CTL的抗病毒作用与其产生的IFN-γ、TNF-α等细胞因子的量密切相关，而肝损伤的严重程度与这些细胞因子的量密切相关。这些结果表明，肝炎的严重程度和病毒清除效率受CTL特性的影响，并且导致每种现象（疾病和病毒清除）的因素是不同的。小鼠HBsAg特异性CTL克隆识别HBsAg第28-39位残基的肽段与L_（1d）分子的结合，并与L_（1d）分子的结合进行比较。尽管不同的TCR bata基因的使用，他们都承认残基33作为TCR接触位点。对于在这个位置上有突变的肽，我们现在正在筛选可以作为拮抗剂工作的肽，或者比野生型肽更具免疫原性的肽。我们认为这些突变肽可以分别用于治疗重型肝炎或作为疫苗打破慢性感染患者的耐受性。

Hepatitis B virus (HBV) transgenic mouse (TgM) was used to analyze immunopathogenesis of viral hepatitis. Hepatic injury after adoptive transfer of HBsAg-specific cytotoxic Tlymphocytes (CTL) to HBV TgM was monitored by measuring serur ALT levels, and anti-viral effect of CTL was monitored by measuring HBV mRNA remaining in the liver of TgM 5 days after the transfer of CTL.Using CTLs with same specificity but with different TCRs and different cytokine profiles, the effects of individual CTLs on disease severity and viral elimination were anlyzed. Anti-viral effect of CTLs well-0correlated with the amount of cytokines produced by CTLs, like IFN-gamma and TNFalpha, however, the severity of hepatic injury did hot correlate with the amount of those cytokines. These results suggest that the severity of hepatitis and the efficiency of viral clearance are affected by the characteristics of CTLs and taht the factors responsible for each phenomenon (disease and viral clearance) are different. The more detailed study is needed to clarify the factor taht is most responsible for the disease exacerbation of hepatitis and to apply those observation to the anti-inflammatory therapy of hepatitis.Murine HBsAg-specific CTL clones recognize the peptide that locates the residue 28-39 of HBsAg in association with L^d molecule. In spite of the different TCR bata gene usage, they all recognize the residue 33 as TCR contact site. with the peptides that have mutations at this position, we are now screening the ones that can work as antagonists, or the ones that are more immunogenic than the wild type peptides. We think that those mutated peptides can be utilized to treat severe hepatitis, or to break tolerance of chronically infected patients as vaccine, respectively.