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Elucidation of pathogenesis and UDCA effect mechanisms in primary biliary cirrhosis

阐明原发性胆汁性肝硬化的发病机制和UDCA作用机制

基本信息

批准号：
04670407
负责人：
MATSUZAKI Yasushi
金额：
$ 1.34万
依托单位：
INSTITUTE OF CLINICAL MEDICINE, UNIVERSITY OF TSUKUBA
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04670407/
关键词：
primary biliary cirrhosis UDCA GVHR cellular immunity MHC class I MHC calss II autoimmune diseases 原発性胆汁性肝硬変 ursodeoxycholic acid MHC classI MHC classII GVHD(GVHR)

项目摘要

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.

我总结了这些调查的结果。首先，我们检测了熊去氧胆酸（UDCA）治疗原发性胆汁性黄疸（PBC）4年以上后的生化和组织学疗效。3例病例显示，在短期UDCA治疗期间，发现肝脏组织学得到改善，血液化学和瘙痒也得到改善，但长期治疗后，尽管生化和瘙痒持续改善，但组织学结果略差。此外，未获得UDCA对MHC I类和II类抗原的一致变化。认为UDCA不能作为PBC的根本治疗手段，但可延缓PBC的临床分期;其次，我们研究了可溶性MHC Ⅰ类抗原的含量与GVHR死亡率的关系，结果表明，可溶性MHC Ⅰ类抗原的测定可用于判断GVHR的严重程度;第三，我们使用具有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作用。与非转基因受者相比，转基因受者的自身免疫样病变减弱。转基因受者的抗PDH抗体水平明显高于非转基因受者。这些结果表明，IL-6在体内过量产生可能调节自身免疫性疾病的进展。在最后一项研究中，为了阐明UDCA的作用机制，我们研究了UDCA和TUDCA处理MHC II类突变小鼠后的细胞免疫学变化。治疗组与未治疗组GVHR程度、MHC Ⅱ类分子表达、CD_4/CD_8比值、ICAM-1表达差异无统计学意义。在PBC模型中，推测UDCA可能不调节细胞免疫。PBC患者血清可溶性MHC Ⅰ类分子水平及IL-6水平的变化有待进一步研究。