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Development of novel therapy against bullous diseases

Research Project

Project/Area Number 10044318
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 Univ. School of Medicine, Dept.of Dermatology, Professor, 医学部, 教授 (50051579)

Co-Investigator(Kenkyū-buntansha) HASHIMOTO Koji  Ehime Univ. School of Medicine, Dept.of Dermatology, Professor, 医学部, 教授 (00110784)
SHIMIZU Hiroshi  Hokkaido Univ. School of Medicine, Dept.of Dermatology, Associate Professor, 医学部, 教授 (00146672)
MASAYUKI Amagai  Keio Univ. School of Medicine, Dept.of Dermatology, Assistant Professor, 医学部, 専任講師 (90212563)
HASHIMOTO Takashi  Kurume Univ. School of Medicine, Dept.of Dermatology, Professor, 医学部, 教授 (20129597)
ブラック マーチン・M  英国セントトマス病院セントジョン皮膚研究所, 部長
スタンレー ジョン・R  米国ペンシルバニア大学, 医学部, 教授
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 1999: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 1998: ¥4,600,000 (Direct Cost: ¥4,600,000)
KeywordsAutoimmune / Inherited skin disease / Desmoglein / Laminin 5 / Type VII collagen / Animal model / Epidermal sheets / Gene therapy / ノックアウトマウス / 遺伝子解析 / 自己免疫皮膚疾患
Research Abstract

This study enhanced international collaboration between groups which lead the fields of investigative dermatology on autoimmune and inherited bullous diseases. In this study, a novel active disease model for pemphigus has been developed. Knockout mice do not acquire tolerance of the defective gene product. Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris (PV), we established a method to generate an active disease model for this autoantibody-mediated disease. Dsg3ィイD1-/-ィエD1 mice, but not Dsg3ィイD1+/-ィエD1 littermates, produced anti-Dsg3 IgG that was able to bind the native Dsg3 when immunized with recombinant mouse Dsg3. Splenocytes from the immunized Dsg3ィイD1-/-ィエD1 mice were then adoptively transferred into Rag-2ィイD1-/-ィエD1 immunodeficient mice expressing Dsg3. Anti-Dsg3 IgG was stably produced in the recipient mice for over 6 months without further boosting. This IgG bound to Dsg3 in vivo and disrupted the cell-cell adhesion of keratinocytes. Consequently, the recipient mice developed erosions in their oral mucous membranes with typical histologic findings of PV. As an innovative therapeutic approach, we have developed chimeric molecules for targeting of antigen-specific B cells in PV. The recombinant toxins fused with Dsg3 could eliminate Dsg3-specific hybridoma cells or anti-Dsg3 IgG producing B cells from immunized mice with a 60% reduction in cell number. For inherited skin diseases, we investigated the correlation between the type of mutations and the phenotype in dominant and recessive dystrophic epidermolysis bullosa. We also set up basic protocol for production of epidermal sheets for clinical application. Several recombinant adenoviruses were developed to introduce exogenous genes to epidermal cells.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] Mahoney MG, Wang Z, Rothenberger KL, Koch PJ, Amagai M, Stanley JR: "Explanation of 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
      1999 Final Research Report Summary
  • [Publications] Wu H, Wang ZH, Yan A, Lyle S, Fakhazadeh S, Wahl JK, Wheelock MJ, Uitto J, Amagai M, Stanley JR.: "Protection of neonates against pemphigus foliaceus by desmoglein3"N Eng. J. Med. (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ishii K, Amagai M, Komai A, et al: "Desmoglein 1 and desmoglein 3 and the target arutoantigens in herpetiform pemphigus"Arch Dermatol.. 135. 943 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Proby CM, Ohta T, Suzuki H, et al: "Development of chimeric molecules for recognition and targeting of antigen-specific B cells in pemphigus vulgaris"Br J Dermatol. (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 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 permphigus"J Clin Invest. (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Amagai M: "Advances in pemphigus foliaceus and pemphigus vulgaris"In D. Dyall-Smith & R. Marks(Eds.), Dermatology at Millennium: Proceeding of 19th World Congress of Dermatology New York: Partheonon Publishing. 812 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 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
      1999 Final Research Report Summary
  • [Publications] Ishii K, Amagai M, Komai A, Ebihara T, Chorzelski TP, Jablonska S, Ohya K, Nishikawa T, Hashimoto T: "Desmoglein 1 and desmoglein 3 are the target autitigens in herpetiform pemphigus."Arch Dermatol. 135. 943-947 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 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. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Wu H, Wang ZH, Yan A, Lyle S, Fakharzadeh S, Wahl JK, Wheelock MJ, Uitto J, Amagai M, Stanley JR.: "Protection of neonates against pemphigus foliaceus by desmoglein 3"N Eng L Med. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 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)

    • Related Report
      1999 Annual Research Report
  • [Publications] Wu H,Wang ZH,Yan A,Lyle S,Fakharzadeh S,Wahl JK,Wheelock MJ,Uitto J,Amagai M, Stanley JR.: "Protection of neonates against pemphigus foliaceus by desmoglein 3"N Eng J Med(in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ishii K,Amagai M,Komai A,et al.: "Desmoglein 1 and desmoglein 3 are the target autoantigens in herpetiform pemphigus"Arch Dermatol. 135. 943-947 (1999)

    • Related Report
      1999 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 enazme-linked immunospot(ELISPOT)Assay:requirement of T cell collaboration for autoantibody production"J Invest Dermatol. 114. 88-94 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Proby CM,Ohta T,Suzuki H,et al.: "Development of chimeric molecules for recognition and targeting of antigen-specific B cells in pemphigus vulgaris"Br J Dermatol. (in press). (2000)

    • Related Report
      1999 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. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Amagai M: "Advabces in pemphigus foliaceus and pemphigus vulgaris"In D.Dyall-Smith&Marks(Eds.)Dermatology at Millennium:Proceeding of 19th World Congress of Dermatology New York:Parthenon Publishing. 812 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hashimoto T,Amagai M,Wang N,Nishikawa T,Karashima T,Moria O,Jabionska S,Chorzeiski TP: "Novel non-radioisotope immunoprecipitation studies indicate involvement of pemphigus vulgaris antigen in paraneoplastic pemphigus" Dermatol Sci. 17. 132-139 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Aamagai 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-desmoglcin autoan-tibody profile" J Am Acad Dermatol. 40. 167-1*0 (1999)

    • Related Report
      1998 Annual Research Report
  • [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)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shimizu H,Takizawa Y,Pulkkinen L,Zone JJ,Matsumoto K,Saida T,Uitto J,Nishikawa T: "The 97 kDa linear IgA bullous dermatosis antigen is not expressed in a patient with generalized atrophic benign epidermolysis bullosa with a novel homozygous G258X mutation in COL17A1" J Invest Dermatol. 111. 887-892 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takizawa Y,shimizu H,Pulkkinen L,Hiraoka Y,McGrath JA,Suzumori K,Aiso: "Novel mutations in the LAMB3 gene shared by two Japanese unrelated families with Herlitz junctional epidermolysis bullosa,and their application for prenatal testing" J Invest Dermatol. 110. 174-178 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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