1998 Fiscal Year Final Research Report Summary
Mechanism of Bile Duct Destruction in Primary Biliary Cirrhosis
| Project/Area Number |
08670621
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Keio University |
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Principal Investigator |
ODA Masaya Keio University, Sch of Med., Dept. of Int.Med., Assistant Professor, 医学部, 講師 (20129381)
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| Co-Investigator(Kenkyū-buntansha) |
FUNATSU Kazuo Keio University, Sch of Med., Dept. of Int.Med., Assistant Professor, 医学部, 講師 (00129644)
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| Project Period (FY) |
1996 – 1998
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| Keywords | PBC / bile duct destruction / cytokaratin subclass CK1 / anti-CK1 antibody / ICAM-1 / LFA-1 / soluble(s) ICAM-1 / UDCA |
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| Research Abstract |
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
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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
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