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2001 Fiscal Year Final Research Report Summary

Development of immune supression against gene product in gene therapy

Research Project

Project/Area Number 11557066
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) KOYASU Shigeo  Keio University, School of Medicine, Professor, 医学部, 教授 (90153684)
OHYAMA Manabu  Keio University, School of Medicine, Lecturer, 医学部, 助手 (10255424)
NISHIKAWA Takeji  Keio University, School of Medicine, Professor, 医学部, 教授 (50051579)
Project Period (FY) 1999 – 2001
KeywordsGene therapy / Inherited disease / Immune response / Autoimmune / Model mouse / Knockout mouse / Skin graft / CD40 ligand
Research Abstract

Gene therapy to treat recessive genodermatoses may provoke unwanted immune response against the introduced gene product because tolerance against this novel protein is absent in patients. In this study, using desmoglein 3 knockout (Dsg3-/-) mice as a disease model for genetic defect of DSG3, we investigated whether immune response against Dsg3 is provoked by nonviral gene therapy and whether such reaction could be prevented. When mouse Dsg3 CDNA was introduced in the skin of Dsg3-/- mice by naked DNA injection, some Dsg3-/- mice developed anti-Dsg3 IgG which bound to Dsg3 expressed by the therapy in vivo. To overcome this problem, we used anti-CD40L monoclonal antibody (MR1) to block co-stimulatory interaction between CD40-CD40L, which is important in the triggering and maintenance of immune responses. For this assay, we employed the Dsg3+/+ skin graft on Dsg3-/- mice to represent stable gene transfer of Dsg3. After skin grafting, all recipient Dsg3-/- mice were treated either with MR1 or with hamster IgG regularly. All of hamster IgG treated mice developed circulating anti-Dsg3 IgG 2-3 weeks after the skin graft. This IgG production lasted: more than 4 weeks and IgG deposition was observed on the surfaces of the keratinocytes in grafts.; However, this anti-Dsg3 IgG production was efficiently suppressed when the recipient mice were treated with MR1. These findings indicate that effective prevention of such undesirable immune response is required for a successful gene therapy for recessive genodermatoses and that the blockade of CD40-CD40L interaction may be a valuable way to achieve this prevention.

  • Research Products

    (13 results)

All Other

All Publications (13 results)

  • [Publications] Amagal 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 Gun Invest. 105. 625-631 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Amagal M, Matsuyoshi N, Wang ZH, Andl C, Stanley JR: "Toxin in bullous impetigo and staphylococcal scalded skin syndrome targets desmoglein 1"Nature Medicine. 6. 1275-1277 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [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(和文)」より
  • [Publications] Sekiguchi M, 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)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsunoda K, Ota I, Suzuki H, Ohyama M, Nagai I, Nishikawa T, Amagai 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
  • [Publications] Ohyama M, Amagai M, Tsunoda K, Ota T, 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
  • [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
  • [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
  • [Publications] Amagai M., Matsuyoshi N., Wang Z.H., Andl C.: "Stanley JR, Toxin in bullous impetigo and staphylococcal scalded skin syndrome targets desmoglein 1"Nature Medicine. 6. 1275-1277 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [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
  • [Publications] Sekiguchi M., 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)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsunoda K., Ota T., Suzuki H. Ohvama 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
  • [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

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Published: 2003-09-17  

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