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Basic studies for development of disease-specific therapeutic strategies against autoimmune diseases

Research Project

Project/Area Number 12470181
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Dermatology
Research InstitutionKeio University

Principal Investigator

NISHIKAWA Takeji  Keio University School of Medicine, Professor, 医学部, 教授 (50051579)

Co-Investigator(Kenkyū-buntansha) ISHIKO Akira  Keio University School of Medicine, Assistant Professor, 医学部, 専任講師 (10202988)
AMAGAI Masayuki  Keio University School of Medicine, Assistant Professor, 医学部, 専任講師 (90212563)
TANAKA Masaru  Keio University School of Medicine, Associate Professor, 医学部, 助教授 (40188339)
ANZAI Hidemi  Keio University School of Medicine, Lecturer, 医学部, 助手 (90276345)
OHYAMA Manabu  Keio University School of Medicine, Lecturer, 医学部, 助手 (10255424)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥16,200,000 (Direct Cost: ¥16,200,000)
Fiscal Year 2001: ¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 2000: ¥9,700,000 (Direct Cost: ¥9,700,000)
KeywordsAutoimmune / Autoantibody / Model mouse / epitope / bullous disease / knockout mouse / pemphigus / desmoglein
Research Abstract

The purpose of this study is to obtain basic knowledge for the development of disease-specific therapeutic strategies against autoimmune diseases. We used pemphigus, an autoimmune blistering diseases of the skin and mucous membranes. Patients with pemphigus vulgaris (PV) and foliaceus (PF) have circulating pathogenic IgG autoantibody against desmoglein. 3 (Dsg3) and desmoglein 1 (Dsg 1), respectively. We took two independent approaches, one was using patients specimen and the other was using a mouse model of pemphigus vulgaris. In the approach using patients specimen, we generated Dsg1- and Dsg3-domain-swapped molecules and point-mutated Dsg3 molecules with Dsg 1-specific residues by baculovirus expression to map conformational epitopes of Dsg 1 and Dsg3 in PF and PV. The binding of autoantibodies to the mutant molecules was assessed by competition ELISA. Domain-swapped molecules containing the N-terminal 161 residues of Dsg1 and Dsg3 yielded greater than 50% competition in 30/43 (69.8%) PF sera and 31/40 (77.5%) PV sera, respectively. Within these N-terminal regions, most of the epitopes were mapped to residues 26-87 of Dsg1 and 25-88 of Dsg3. These findings suggest that the dominant autoimmune epitopes in both PF and PV are found in the N-terminal adhesive surfaces of Dsgs. In the approach using the PV mouse model, we succeeded in obtaining several anti-Dsg3 mouse monoclonal IgG antibodies from the PV model mice. Among them AK19 and AK23 showed the pathogenic activity in inducing blister formation. At this point we could not obtain any specific peptides to bind these pathogenic antibodies. Through these studies we could obtain important tools to develop the disease-specific immune suppressive therapy.

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Amagal M, Tsunoda K, Suzuki H, Nishifuji K, Koyasu S, Nishikawa I: "Use of autoantigen knockout mice to develop an active autoimmune disease model of pemphigus"J Clin Invest. 105. 625-631 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Futel Y, Amagal M, Sekiguchi M, Nishifuji K, Fujii Y, Nishikawa T: "Conformational eptiope mapping of desmoglein 3 using domain-swapped molecules in pemphigus vulgaris"J Invest Dermatol. 115. 829-834 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sekiguchi M, Futel Y, Fujil Y, Iwasaki T, Nishikawa T, Amagal M: "Dominant autoimmune epitopes recognized by pemphigus antibodies map to the N-terminal adhesive region of desmogleins"J Immunol. 167. 5439-5448 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Futei Y, Amagal M, Ishil K, Kuroda-Kinoshita K, Ohya K, Nishikawa I: "Predominant IgG4 subclass in autoantibodies of pemphigus vulgaris and foliaceus"J Dermatol Sci. 26. 55-61 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tsunoda K, Ota T, Suzuki H, Ohyama M, Nagai T, Nishikawa I, Amagal M: "Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental"Eur J Immunol. 32. 627-633 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ohyama M, Amagai M, Isunoda K, Ota I, Koyasu S, Umezawa A, Hata J: "Immunologic and histopathologic characterization of active disease mouse model for pemphigus vulgaris"J Invest Dermatol. 118. 199-204 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 天谷雅行: "免疫2002"自己抗原ノックアウトマウスを用いた新たな自己免疫疾患モデル動物. 265 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Amagai M., Tsunoda K., Suzuki H., Nishifuji K., Koyasu, S., Nishikawa T.: "Use of autoantigen knockout mice to develop an active autoimmune disease model of pemphigus"J Clin Invest. 105. 625-631 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Futei Y., Amagai M., Sekiguchi M., Nishifuji K., Fujii Y., Nishikawa T.: "Conformational eptiope mapping of desmoglein 3 using domain-swapped molecules in pemphigus vulgaris"J Invest Dermatol. 115. 829-834 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sekiguchi M., Futei Y., Fujii Y., Iwasaki T., Nishikawa T., Amagai M.: "Dominant autoimmune epitopes recognized oy pempmgus antioooies map to the N-terminal adhesive region of desmogleins"J Immunol. 167. 5439-5448 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Futei Y., Amagai M., Ishii K., Kuroda-Kinoshita K., Ohya K., Nishikawa T.: "Predominant IgG4 subclass in autoantibodies of pemphigus vulgaris and foliaceus"J Dermatol Sci. 26. 55-61 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tsunoda K., Ota T., Suzuki H., Ohyama M., Nagai T., Nishikawa T., Amagai M., Koyasu S.: "Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental pemphigus vulgaris"Eur J Immunol. 32. 627-633 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ohyama M., Amagai M., Tsunoda K., Ota T., Koyasu S., Umezawa A., Hata J., Nishikawa T.: "Immunologic and histopathologic characterization of active disease mouse model for pemphigus vulgaris"J Invest Dermatol. 118. 199-204 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sekiguchi H, Futei Y, Fujii Y, Iwasaki T, Nishikawa T, Amagai M: "Dominant autoimmune epitopes recognized by pemphigus antibodies map to the N-terminal adhesive region of desmogleins"J Immunol. 167. 5439-5448 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsunoda K, Ota T, Suzuki H, Ohyama M, Nagai T, Nishikawa T, Koyasu S: "Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental pemphigus vulgaris"Eur J Immunol. 32. 627-633 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Amagai M, Yamaguchi T, Hanakawa Y, Nishifuji K, Sugai H, Stanley JR: "Staphylococcal Exfoliative Toxin B Specifically Cleaves Desmoglein 1"J Invest Dermatol. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Ohyama M, Amagai M, Tsunoda K, Ota T, Koyasu S, Unezawa A, Hata J, Nishikawa T: "Immunologic and histopathologic characterization of active disease mouse model for pemphigus vulgaris"J Invest Dermatol. 118. 199-204 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Futei Y, Amagai M, Ishii K, Kuroda-Kinoshita K, Ohya K, Nishikawa T: "Predominant IgG4 subclass in autoantibodies of pemphigus vulgaris and foliaceus"J Dermatol Sci. 26. 55-61 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 天谷雅行: "免疫2002"自己抗原ノックアウトマウスを用いた新たな自己免疫疾患モデル動物. 265 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Amagai M,Tsunoda K,Suzuki H,Nishifuji K,Koyasu S,Nishikawa T: "Use of autoantigen knockout mice to develop an active autoimmune disease model of pemphigus."J Clin Invest. 105. 625-631 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Futei Y,Amagai M,Sekiguchi M,Nishifuji K,Fujii Y,Nishikawa T: "Conformational eptiope mapping of desmoglein 3 using domain-swapped molecules in pemphigus vulgaris."J Invest Dermatol. 115. 829-834 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Proby CM,Ohta T,Suzuki H,Koyasu S,Gamou S,Shimizu N,Wheelock MJ,Nishikawa T,Amagai M: "Development of chimeric molecules for recognition and targeting of antigen-specific B cells in pemphigus vulgaris."Br J Dermatol. 142. 321-330 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nishifuji K,Amagai M,Kuwana M,Iwasaki T,Nishikawa T: "Detection of antigen-specific B cells in patients with pemphigus vulgaris by enzyme-linked immunospot (ELISPOT) Assay : requirement of T cell collaboration for autoantibody production."J Invest Dermatol. 114. 88-94 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hakuno M,Shimizu H,Akiyama M,Amagai M,Wahl JK,Wheelock MJ,Nishikawa T: "Dissociation of intra-and extracellular domains of desmosomal cadherins and E-cadherin in Hailey-Hailey disease and Darier's disease."Br J Dermatol. 143. 702-711 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Futei Y,Amagai M,Ishii K,Kinoshita K,Ohya K,Nishikawa T: "Predominant IgG4 subclass in autoantibodies of pemphigus vulgaris and foliaceus."J Dermatol Sci. (in press). (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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