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MOLECULAR MECHANISM OF IMMUNE REGULATION IN PRIMARY BILIARY CIRRHOSIS

Research Project

Project/Area Number 08457155
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 内科学一般
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

ISHIBASHI Hiromi  KYUSHU UNIVERSITY,FACULTY OF MEDICINE,ASSOCIATE PROFESSOR, 医学部, 助教授 (80127969)

Co-Investigator(Kenkyū-buntansha) NISHIMURA Yasuharu  KUMAMOTO UNIVERSITY,FACULTY OF MEDICINE,PROFESSOR, 医学部, 教授 (10156119)
HAYASHIDA Kazuhiro  KYUSHU UNIVERSITY,FACULTY OF MEDICINE,INSTRUCTOR, 医学部, 助手 (60180981)
NAKAMURA Minoru  KYUSHU UNIVERSITY,FACULTY OF MEDICINE,INSTRUCTOR, 医学部, 助手 (40217906)
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 1997: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1996: ¥3,800,000 (Direct Cost: ¥3,800,000)
KeywordsPrimary biliary cirrhosis / Autoimmune disease / Immune regulation / T cell / T cell receptor / T cell epitope / Molecular mimicry / Immune response / HLA
Research Abstract

1.Mapping of B cell epitope of mitochondrial antigen.
Using anti-mitochondrial antibody obtained from the oatient with primary biliary cirrhosis (PBC), we performed epitope mapping of a major mitochondrial antigen, E2 component of pyruvate dehydrogenase complex (PDC-E2). The epitopes are mapped in the regions around lipoic acid-bound lysine in the outer and innner lypoil domains. Each Asp of the N-terminal side is important to bind antibody. Lypoic acid did not influence immunoreactivity with the antibody.
2.Cloning of T cell specific for mitochondrial antigen epitope mapping.
We established six T cell clones specific for PDC-E2 peptides from four different patients with PBC using 33 different peptides of 17-20 amino acid residues corresponding to human PDC-E2 as stimulating antigens (Ags). The minimal T cell of these six T cell clones were all mapped to the same region of the PDC-E2 peptide 163-176 (GDLLAEIETDKATI). The common essential amino acids of this epitope for these T cell clones … More were E,D and K at positions 170,172 and 173, respectively. One T cell clone cross-reacted to exogenous Ags such as E.coli PDC-E2 peptide which has an EXDK sequence. This is the definite demonsration of the presence of molecular mimicry at the T cell clonal level in human autoimmune diseases.
T cell receptor
We found that frequency of the T cells reactive to the human PDC-E2 163-176 peptide is significantly increased in the peripheral blood of patients with PBC as compared to healthy subjects. We also confirmed that these T cells were all restricted with HLA-DRB4^<**>01 (DR53). These results together with the evidence that the immunodominant B cell epitope overlaps with the human T cell epitope of the PDC-E2 antigen indicate that the T cells reactive to this epitope are closely associated with the pathogenesis of PBC.The Vbeta-and the Jbeta-gene usages were diverse among the T cell clones (Vbeta11-Lbeta1.4, Vbeta8-Jb1.2, Vbeta12-Jb2.1, Vbeta10-Jbeta1.5 and Vbeta20-Jbeta2.1). By contrast, in the third complementarity determining region (CDR3), G was frequently found and GXG or GXS motif was identified in all T cell clones. Moreover, RGXG motif was found in three clones generated from two patients.These results indicate that the T cells may recognize the ligand (the human PDC-E2 163-176 peptide/HLA-DR53 complex) using the limited motif in the CDR3 region and that the design of CDR3-specific immunotherapy wouled be possible using these motifs. Less

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Ichiki, Y., Shimoda, S., Hara, H., Sigemats, K., Nakamura, M., Hayashida.K, .Ishibashi, H., Niho, Y.: "Analysis of T Cell Receptor β of the T Cell Clones Reactive to the Human PDC-E2 163-176 Peptide in the context of HLA-DR53 in Patients with Primary Biliary Cirrhosis" Hepatology. 26. 728-733 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kichiko Koike, Shinji Shimoda, Hiromi Ishibashi, Masahiko Koike: "Mammalian 2-oxo acid dehydrogenase complexes as autoantigen in primary biliary cirrhosis." Biochemistry and Physiology of Thiamine Diphosphate Enzymes.Edit.H.Bisswanger,A Scellenberger,A.u.C.Intemann.Wissenchaftlicher Verlag,Prien. 418-423 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Koike, K., Ishibashi, H., Koike, M.: "Immunoreactivity of porcine heart dihydrolipoamide acetyl-and succinyl-transferases(PDC-E2,OGDC-E2)with primary biliary cirrhosis sera:Characterization of the autoantigenic region and effects of enzymatic delipoylation and relipoylation." Hepatology. 27(in press). (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 石橋 大海, 下田 慎治, 中村 稔, 林田 一洋, 仁保 喜之: "原発性胆汁性肝硬変における自己反応性T細胞とエピトープ解析" Biotherapy. 10. 1272-1279 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 一木 康則、下田 慎治、重松 宏尚、中村 稔、林田 一洋、石橋 大海、仁保 喜之: "原発性胆汁性肝硬変患者末梢血のPDC-E2ペプチド反応性T細胞と分子相同性" 消化器と免疫. 33. 177-180 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Shimoda, S., Van de Water, J., Ichiki, Y., Shigematsu, H., Nakamura, M., Ansari, A.A., Ishibashi, H., Gershwin, M.E.: "The T cell immunobiology of primary biliary cirrhosis." Molecular and genetic approaches to Diseases-Immunology,Hematology and Oncology,edit.Y,Niho,Kyushu University Press,Fukuoka. (in press). (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ichiki, Y., Shimoda, S., Hara, H., Sigematsu, K., Nakamura, M., Hayashida, K., Ishibashi, H M., Niho, Y.: "Analysis of T cell receptor of the T cell clones reactive to the human PDC-E2 163-176 peptide in the context of HLA-DR53 in patients with primary biliary cirrhosis." Hepatology. 26(3). 728-733 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kichiko Koike, Shinji Shimoda, Hiromi Ishibashi, Masahiko Koike: "Mammalian 2-oxo acid dehydrogenase complexes as autoantigen in primary biliary cirrhosis." Biochemistry and Physiology of Thiamine Diphosphate Enzymes, Edit.H.Bisswanger, A Scellenbeger, A.u.C.Intemann Wissenchaftlicher Verlag, Prien. 418-423 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Koike, K., Ishibashi, H., Koike, M.: "Immunoreactivity of porcine heart dihydrolipoamide acetyl-and succinyl-transferases (PDC-E2, OGDC-E2) with primary biliary cirrhosis sera : Characterization of the autoantigenic region and effects of enzymatic delipoylation and relipoylation." Hepatology. 27(in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ishibashi, H., Shimoda, S., Nakamura, M., Mayashida, K., Niho, Y.: "Autoreactive T cell and its epitope in primary biliary cirrhosis" Biotherapy. 10(10). 1272-1279 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ishibashi, H.: "Anti-mitochondrial antibody-its pathological role." Autoimmune Liver Diseases-Pathophisyology and Treatment. Shinko Igaku Shuppan, Tokyo. 150-157 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ichiki, Y., Shimoda, S., Sigematsu, K., Nakamura, M., Hayashida, K., Ishibashi, H., Niho, Y.: "PDC-E2 reptide reactive T cells and molecular mimicry in primary biliary cirrhosis." Gastroenterology and Immunology 33, My Life. 177-180 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ishibashi, H., Mukai, T., Hayashida, K.: "Primary biliary cirrhosis and HLA-Analysis of HLA class II DNA polymorhism." "Apoptosis, Adhesion molecule, HLA" in Biochemistry of the Liver-Hakone symposium 7, Chugai Igakusha. 169-177 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Shimoda, S., Van de Water, J., Ichiki, Y., Shigematsu, H., Nakamura, M., Ansari, A.A., Ishibashi, H., Gershwin, M.E.: "The T cell immunobiology of primary biliary cirrhosis" Molecular and genetic approaches to Diseases-Immunology, Hematology and Oncology, edit. Y.Niho, Kyushu University Press, Fukuoka. (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ichiki,Y.,Shimoda,S.,Hara,H.,Sigematsu,K.,Nakamura,M.,Hayashida,K.,Ishibashi,H.,Niho,Y.: "Analysis of T Cell Receptor β of the T Cell Clones Reactive to the Human PDC-E2 163-176 Peptide in the context of HLA-DR53 in Patients with Primary Biliary Cirrhosis" Hepatology. 26. 728-733 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kichiko Koike,Shinji Shimoda,Hiromi Ishibashi,Masahiko Koike: "Mammalian 2-oxo acid dehydrogenase complexes as autoantigen in primary biliary cirrhosis." Biochemistry and Physiology of Thiamine Diphosphate Enzymes.Edit.H.Bisswanger,A Scellenberger,A.u.C.Intemann,Wissenchaftlicher Verlag,Prien. 418-423 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Koike,K.,Ishibashi,H.,Koike,M.: "Immunoreactivity of porcine heart dihydrolipoamide acetyl-and succinyl-transferases(PDC-E2,OGDC-E2)with primary biliary cirrhosis sera:Characterization of the autoantigenic region and effects of enzymatic delipoylation and relipoylation." Hepatology. 27. in press (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 石橋大海,下田慎治,中村 稔,林田一洋,仁保喜之: "原発性胆汁性肝硬変における自己反応性T細胞とエピトープ解析" Biotherapy. 10. 1272-1279 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] 一木康則、下田慎治、重松宏尚、中村 稔、林田一洋、石橋大海、仁保喜之: "原発性胆汁性肝硬変患者末梢血のPCD-E2ペプチド反応性T細胞と分子相同性" 消化器と免疫. 33. 177-180 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Shimoda,S.,Van de Water,J.,Ichiki,Y.,Shigematsu,H.,Nakamura,M.,Ansari,A.A.,Ishibashi,H.,Gershwin,M.E.: "The T cell immunobiology of primary biliary cirrhosis." Molecular and genetic approaches to Diseases-Immunology,Hematology and Oncology,edit.Y.Niho,Kyushu University Press,Fukuoka. in press (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ichiki,Y.,Shimoda,S.,Hara,H.,Sigematsu,K.,Nakamura,M.,Hayashida,K.,Niho,Y.,Ishibashi,H.: "Analysis of T Cell Receptor b of the T Cell Clones Reactive to the Human PDC-E2 163-176 Peptide in the context of HLA-DR53 in Patients with Primary Biliary Cirrhosis" Hepatology. 25. (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] 一木康則、下田慎治、重松宏尚、中村 稔、林田一洋、石橋大海、仁保喜之: "原発性胆汁性肝硬変患者末梢血のPDC-E2ペプチド反応性T細胞と分子相同性" 消化器と免疫. 31. 183-186 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 石橋大海: "〈原発性胆汁性肝硬変 免疫異常〉抗ミトコンドリア抗体とその病因的意義" 自己免疫性肝疾患-その病態と治療-. 150-157 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 石橋大海,下田慎治,松井美詠子,中村 稔,林田一洋,小池吉子: "ミトコンドリア抗原のエピトープ解析" 肝免疫療法の進歩. 3. 57-68 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 下田慎治,中村 稔,林田一洋,石橋大海,仁保喜之: "原発性胆汁性肝硬変の自己抗原としてのPyruvate-Dehydrogenase Complex" 臨床免疫. 28. 624-630 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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