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Mechanism of Bile Duct Destruction in Primary Biliary Cirrhosis

原发性胆汁性肝硬化胆管破坏的机制

基本信息

批准号：
08670621
负责人：
ODA Masaya
金额：
$ 1.54万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

1) The monoclonal antibody was produced against cytokeratin subclass CK1 (52KD) obtained from the successive human cultured cell line PtK_2. By the indirect immunoperoxidase method using anti - CK1 antibody, the expressions of CK1 were examined in the laparoscopic wedged liver biopsy specimens from patients with primary biliary cirrhosis (PBC) and from those with non - icteric cholelithiasis. CK1 was aberrantly expressed in the septal and interlobular bile duct epithalial cells featured by chronic nonsuppurative destructive cholangitis (CNSDC) in antimitochomdrial antibody (AMA)-positive and AMA-negative PBC, while CK1 was not expressed throughout the intrahepatic biliary tract in the conrtol, implying that CK1 may play a role as "an epitope" to triggre the autoimmune destructive response targeting the septal and interlobular bile ducts in PBC.2) Imnunohistochemical expressions of intercellular adhesion molecule (ICAM-1) and its ligand, lymphocyte function-associated antigen (LFA-1) we … More re examined in the wedged liver biopsy specimesd in PBC and in the control as above, while ICAM-1 was expressed only in the hepatic sinusoidal endothelial cells in the control. ICAM-1 was aberrantly expressed in the epithelial cell plasma membranes of the interlobular and septal ltle ducts, particularly in the basal site of the epithelial cell plasma membranes of the bile ducts intensely infiltrated with lymphocytes. LFA-1 was strongly expressed on the surfaces of lymphocytes intensely infiltrated around the bile ducts showing CNSDC. Some of the LFA-1-povitive lynphocytes were found to be directly attached on the basal sites of the bile ducts epithelial cell plasma membranes. Some of the CD4-positive, CD8-positive lymphocytes identified by the immunoperexidase method were evident on the basal and lateral surface of the injured bile duct elithelial cells. Moreover, not only the enhanced expressions of HLA-A, B and C but also the aberrant expressions of HLA-DR were noted in the duct epithelial cells showing CNSDC. Based on the above findings, both of the activated CD4-positive (MHC class II-restricted) and CD8-positive (MHC class I-restricted) T cells would directly or indirectly act on the target epithelial cells of the interlobular and septal bile duct under the aberrant expression of HLA-DR and the enhancement of HLA-A, B, C. The interactions between the ICAM-1 on the bile duct epithelium and the LFA-1 on CD4-positive and CD8-positive lymphocyte surfaces is considered to be a key immune process for the bile duct destruction in PBC.3) Another study was conducted to elucidate how ursodeoxycholic acid(UDCA) therapy (600mg/day) for PBC patients affects the serum anti-CK-1 antibody titers determined by sandwich inhibition ELISA as well as the soluble(s)-ICAM-1 levels determined by ELISA in the sera of PBC patients, reflecting the above immunchistorhemical expressions of ICAM-1. Both of the anti-CK1-titers and s-ICAM-1 levels were significantly decraosed one month after the treatment with UDCA, and maintained at the lower levels during the twenty four months of UDCA treatment, indicating that the long-term UDCA therapy would be involved in the improvement of autoimmune bile duct destruction. Less

1)从连续培养的人细胞系PtK_2中获得抗细胞角蛋白亚类CK_1（52 KD）的单克隆抗体。应用抗CK 1抗体的间接免疫过氧化物酶法检测原发性胆汁性肝硬化（PBC）和非黄疸型胆石症患者腹腔镜肝活检标本中CK 1的表达。在抗线粒体抗体（AMA）阳性和阴性的PBC中，CK 1在以慢性非化脓性破坏性胆管炎（CNSDC）为特征的隔胆管和小叶间胆管上皮细胞中异常表达，而在对照组中，CK 1在整个肝内胆管中不表达，这意味着CK 1可能作为“表位”发挥作用，2）免疫组化法检测细胞间粘附分子-1（ICAM-1）及其配体的表达，淋巴细胞功能相关抗原（LFA-1） ...更多信息 PBC组和对照组肝活检组织中ICAM-1的表达与上述结果一致，而对照组仅在肝窦内皮细胞中表达ICAM-1。ICAM-1异常表达于小叶间管和隔管上皮细胞质膜，尤其是淋巴细胞浸润较强的胆管上皮细胞质膜基底部。LFA-1强表达于胆管周围淋巴细胞的表面，显示CNSDC。部分LFA-1阳性淋巴细胞直接附着在胆管上皮细胞质膜的基底部位。一些CD 4阳性，CD 8阳性淋巴细胞鉴定的免疫过氧化物酶法是明显的基底和侧面的损伤胆管上皮细胞。在CNSDC的导管上皮细胞中，不仅HLA-A、B、C的表达增强，而且HLA-DR的表达异常。因此，在HLA-DR异常表达和HLA-A、B、C增强的情况下，活化的CD 4阳性（MHC Ⅱ类限制性）和CD 8阳性（MHC Ⅰ类限制性）T细胞可直接或间接作用于小叶间和间隔胆管的靶上皮细胞。胆管上皮细胞表面ICAM-1与CD 4阳性和CD 8阳性淋巴细胞表面LFA-1的相互作用被认为是PBC中胆管破坏的关键免疫过程。3）另一项研究旨在阐明熊去氧胆酸（UDCA）治疗（600 mg/d）对PBC患者血清抗CK-1抗体滴度及可溶性ICAM-1的影响ELISA法检测PBC患者血清中ICAM-1的水平，反映了PBC患者血清中ICAM-1的上述免疫组化表达。UDCA治疗后1个月，抗CK 1滴度和s-ICAM-1水平均明显下降，并在UDCA治疗24个月期间维持在较低水平，提示长期UDCA治疗可能参与改善自身免疫性胆管破坏。少