Elucidation of pathogenesis and UDCA effect mechanisms in primary biliary cirrhosis

我总结了这些调查的结果。首先，我们检查了熊去氧胆酸（UDCA）治疗原发性胆汁性肝硬化（PBC） 4年多后的生化和组织学疗效。3例患者在UDCA短期治疗期间肝脏组织学、血液化学和瘙痒症状均有改善，但长期治疗后组织学结果略差，尽管生物化学和瘙痒症状持续改善。此外，UDCA对MHC I类和II类抗原的改变也不一致。认为UDCA不是治疗PBC的根本方法，而是延缓PBC临床分期的进展。其次，我们研究了可溶性MHC I类抗原的数量是否与GVHR的死亡率有关系。结果表明，测定可溶性MHC I类抗原可用于判断GVHR的严重程度。第三，我们采用MHC II类差异的小鼠GVHR模型，检测了白细胞介素-6（IL-6）对自身免疫性疾病发展的影响。与非转基因受体相比，转基因受体的自身免疫样病变减弱。相比之下，转基因受体的抗pdh抗体明显高于非转基因受体。这些结果表明，体内过量产生的IL-6可能调节自身免疫性疾病的进展。在最后的研究中，为了阐明UDCA的作用机制，我们研究了UDCA和TUDCA处理后MHC II类突变小鼠的细胞免疫学变化。治疗组与非治疗组间GVHR程度、MHCⅱ类表达、CD4/CD8比值、ICAM-1表达差异无统计学意义。在PBC模型中，假设UDCA可能不调节细胞免疫。关于PBC患者可溶性MHC I类水平和IL-6的研究还需要进一步的研究。

I summarized the results of these investigations. First, we examined the efficacy of biochemical and histology after more than 4 yrs of ursodeoxycholic acid(UDCA)treatment in primary biliary chirrhosis(PBC). Three cases show that liver histology was found to be improved, as were blood chemistry and pruritus, during short-term UDCA treatment, but histology results were slightly worse after long-term treatment despite the sustained improvement in biochemistry and pruritus. Moreover, consistent changes of MHC class I and II antigens by UDCA were not obtained. It is supposed that UDCA is not fundamental treatment, but delay the progression of the clinical stage of PBC.Second, we studied wherther the amount of soluble MHC class I antigen shows the relation between the mortality of GVHR.Our results indicates that measurement of soluble MHC calss I antigen is uesful for deciding the severity of GVHR.Third, we examined the effect of interleukin-6(IL-6) on the development of autoimmune diseases employing murine GVHR model with MHC class II disparity. Autoimmune like lesions in transgenic recipients became weakened as compared with those in non-transgenic recipients. In contrast, anti-PDH antibody in transgenic recipients were significantly higher than that of non-transgenic recipients. These results indicate that IL-6 excessively produced in vivo might regulate the progression of autoimmune diseases. In the last study, in order to elucidate the UDCA effect mechanisms, we studied the cellular immunological changes after UDCA and TUDCA treatment in MHC class II mutant mice. We could not recognize that the degree of GVHR, the expression of MHC class II, CD4/CD8 ratio and ICAM-1 between treatment group and non-treament group. In the PBC model, it is supposed that UDCA may not regulate the cellular immunity. Further studies regarding the soluble MHC calss I level and IL-6 in PBC patients, are needed.