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例病例显示，在短期UDCA治疗期间，肝脏组织学、血液生化和瘙痒得到改善，但长期治疗后，尽管生化和瘙痒持续改善，但组织学结果稍差。此外，UDCA对MHC I类和II类抗原的一致变化没有获得。推测UDCA不是根本治疗，而是延缓PBC临床分期的进展。其次，我们研究了可溶性MHC I类抗原的量是否与GVHR死亡率之间的关系。我们的结果表明，可溶性MHC I类抗原的测量有助于判断GVHR的严重程度。第三，我们用小鼠研究了白细胞介素6（IL-6）对自身免疫性疾病发展的影响。具有 MHC II 类差异的 GVHR 模型。与非转基因受者相比，转基因受者的自身免疫样病变减弱。相比之下，转基因受者的抗PDH抗体明显高于非转基因受者。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。在上一项研究中，为了阐明UDCA的作用机制，我们研究了MHC II类突变小鼠经UDCA和TUDCA治疗后细胞免疫学的变化。我们无法识别治疗组与非治疗组之间的GVHR程度、MHC II类表达、CD4/CD8比值和ICAM-1。在PBC模型中，推测UDCA可能不调节细胞免疫。需要进一步研究 PBC 患者中可溶性 MHC I 类水平和 IL-6。

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.