IMMUNO-PATHOGENESIS AND-THERAPY OF VIRAL HEPATITIS

用乙肝病毒转基因小鼠(TGM)分析病毒性肝炎的免疫发病机制。通过检测血清ALT水平来监测过继转移HBs Ag特异性细胞毒性T淋巴细胞(CTL)对肝脏的损害，通过检测CTL转移后5天肝组织中残留的HBVm RNA来监测CTL的抗病毒作用。CTL的抗病毒作用与其产生的细胞因子(如干扰素-γ、肿瘤坏死因子α)呈正相关，而肝损伤的严重程度与这些细胞因子的量呈正相关。这些结果表明，肝炎的严重程度和病毒清除效率受CTL的特性和THTH的影响，导致每种现象的因素(疾病和病毒清除)是不同的。需要更详细的研究来阐明导致肝炎病情恶化的最主要因素，并将这些观察结果应用于肝炎的抗炎治疗。小鼠乙肝表面抗原特异性CTL克隆识别与L^d分子相关的位于乙肝表面抗原28-39位的多肽。尽管TCR BATA基因的用法不同，但它们都识别33位残基为TCR接触位点。对于在这个位置发生突变的多肽，我们现在正在筛选那些可以作为拮抗剂的多肽，或者那些比野生型多肽更具免疫原性的多肽。我们认为，这些突变的多肽可以作为疫苗分别用于治疗重型肝炎和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.