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Development of antigen-specific B cell elimination by recombinant toxins in autoimmune diseases

Research Project

Project/Area Number 09557064
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Dermatology
Research InstitutionKeio University

Principal Investigator

AMAGAI Masayuki  Keio University, School of Medicine, Assistant Professor, 医学部, 専任講師 (90212563)

Co-Investigator(Kenkyū-buntansha) TAKAYANAGI Atsushi  Keio University, School of Medicine, Instructor, 医学部, 助手 (80245464)
SHIMIZU Nobuyoshi  Keio University, School of Medicine, Professor, 医学部, 教授 (50162706)
SHIMIZU Hiroshi  Keio University, School of Medicine, Associate Professor, 医学部, 助教授 (00146672)
NISHIKAWA Takeji  Keio University, School of Medicine, Professor, 医学部, 教授 (50051579)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥12,100,000 (Direct Cost: ¥12,100,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1997: ¥10,500,000 (Direct Cost: ¥10,500,000)
KeywordsAutoimmune disease / Pemphigus / B cell / Disease-specific therapy / Recombinant toxin / Cadherin / Desmoglein / Cell adhesion
Research Abstract

Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by circulating pathogenic IgG antibodies against desmoglein 3 (Dsg3). The purpose of this study was to develop chimeric molecules for specific recognition and elimination of autoimmune B cells in PV.Mouse hybridoma cell lines producing anti-Dsg3 antibody (5H10, 12A2) were developed as an in vitro model system for B cell targeting. Dsg3-GFg a baculoprotein containing the entire extracellular domain of Dsg3 fused with green fluorescence protein, recognized and targeted the hybridoma cells through their surface immunoglobulin receptors in an antigen-specific way. The epitopes of these monoclonal antibodies were mapped on the amino-terminal EC1 and part of EC2, a region considered functionally important in cadherins. Chimeric toxin molecules containing the mapped region (Dsg3_N1) and modified Pseudomonas exotoxin (PE) were produced in bacteria (Dsg3_N1-PF4O-KDEL, PE37-Dsg3_N1-KDEL) and tested in vitro on hybridoma cell lines. The chimeric toxins, but not Dsg3_N1 alone, showed dose-dependent toxic activity with a reduction in hybridoma cell number to 40-60% of toxin-negative control cultures, compared with little or no effect on anti-Dsg3-negative hybridoma cells. Furthermore, these toxins showed toxic effects on anti-Dsg3 IgG-producing B cells from Dsg3_N1-immunized mice, with a 60% reduction in cell number compared with Dsg3_N1 alone. Thus specific recognition and targeting of antigen-specific B cells in PV was demonstrated and this strategy may hold promise as a future therapeutic option for PV and other autoimmune diseases.

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Ishii K, Amagai M, Hall RP, Hashimoto T, Takayanagi A, Gamou S, Shimizu N, Nishikawa T: "Characterization of autoantibodies in pemphigus using antigen-specific ELISAs with baculovirus expressed recombinant desmogleins" J Imunol. 159. 2010-2017 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hertl M, Karr RW, Amagai M, Katz SI: "Heterogeneous MHC II restriction pattern of autoreactive desmoglein 3 specific T cell responses in pemphigus vulgaris patients and normals" J Invest Dermatol. 110. 388-392 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Amagai M, Nishikawa T, Nousari HC, Anhalt GJ, Hashimoto T: "Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice" J Clin Invest. 102. 775-782 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T: "The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile" J Am Acad Dermatol. 40. 167-170 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Proby C, Fujii Y, Owaribe K, Nishikawa T, Amagai M: "Human autoantibodies against HD1/plectin in paraneoplastic pemphigus" J Invest Dermatol. 112. 153-156 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mahoney MG, Wang Z, Rothenberger KL, Koch PJ, Amagai M, Stanley JR: "Explanation for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris" J Clin Invest. 103. 461-468 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ishii K,Amagai M,Hall RP,Hashimoto T,Takayanagi A,Gamou S,Shimizu N,Nishikawa T: "Characterization of autoantibodies in pemphigus using antigen-specific ELISAs with baculovirus expressed recombinant desmogleins." J Immunol. 159. 2010-2017 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hertl M,Karr RW,Amagai M,Katz SI: "Heterogeneous MHC II restriction pattern of autoreactive desmoglein 3 specific T cell responses in pemphigus vulgaris patients and normals." J Invest Dermatol. 110. 388-392 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Amagai M,Nishikawa T,Nousari HC,Anhalt GJ,Hashimoto T: "Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholy-sis in vivo in neonatal mice." J Clin Invest. 102. 775-782 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Amagai M,Tsunoda K,Zillikens D,Nagai T,Nishikawa T: "The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile." J Am Acad Dermatol. 40. 167-170 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Proby C,Fujii Y,Owaribe K,Nishikawa T,Amagai M: "Human autoantibodies against HD1/plectin in paraneoplastic pemphigus." J Invest Dermatol. 112. 153-156 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mahoney MG,Wang Z,Rothenberger KL,Koch PJ,Amagai M,Stanley JR: "Explanation for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris." J Clin Invest. 103. 461-468 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hertl M, Karr Rw, Amagai M, Katz SI: "Heterogeneous MHC II restriction pattern of autoreactive desmoglein 3 specific T cell responses in pemphigus vulgaris patients and normals" J Invest Dermatol. 110. 388-392 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Amagai M, Nishikawa T, Nousari HC, Anhalt GJ, Hashimoto T: "Antibodies against desmoglein 3(pemphigus vulgaris antigen)are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice" J Clin Invest. 102. 775-782 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T: "The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile" J Am Acad Dermatol. 40. 167-170 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Proby C, Fujii Y, Owaribe K, Nishikawa T, Amagai M: "Human autoantibodies against HD 1/plectin in paraneoplastic pemphigus" J Invest Dermatol. 112. 153-156 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mahoney MG, Wang Z, Rothenberger KL, Koch PJ, Amagai M, Stanley JR: "Explanation for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris" J Clin Invest. 103. 461-468 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Amagai M, Komai A, Hashimoto T, Shirakata Y, Hashimoto K, Yamada T, KitajimaY, Ohya K, Iwanami H, Nishikawa T: "Usefulness of enzyme-linked immunosorbent assay(ELISA)using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus" Br J Dermatol. 140. 351-357 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hernandez C, Amagai M, Woodley DT, Chan LS: "Pemphigus foliaceus:preferential binding of IgG1 and C3 at the upper epidermis..." Br J Dermatol. 136. 249-252 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kubo A, Amagai M, Hashimoto T, Doi T, Higashiyama M, Hashimoto K, Yoshikawa K: "Herpetiform pemphigus showing reactivity with pemphigus vulgaris antigen(desimoglein 3)" Br J Dermatol. 137. 109-113 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ishii K, Amagai M, Hall BP, Hashimoto T, Takayanagi A, Gamou S, Shimizu S, Nishikawa T: "Characterization of autoantibodies in pemphigus using antigen-specific ELISAs with baculovirus expressed recombinaut desmogleins." J Immunol. 159. 2010-2017 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hashimoto T.et al: "Human desmocollin 1(Dsc1)is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus." J Invest Dermatol. 109. 127-131 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Shirakata Y, Amagai M,Hanakawa Y, Nishikawa T, Hashimoto K.: "Lack of mucosal involument in pemphigus foliaceus may be due to low expression of desmoglein 1." J Invest Deranatol. 110. 76-78 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hertl M, Amagai M, Sundarain H, Stanley JR, Ishii K, Katz SI: "Recognition of desmoglein 3 by autoreactive T cells in peinphigus vulgaris patients and normals." J Invest Dermatol. 110. 62-66 (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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