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Research of molecular biology and gene therapy for Rheumatoid arthritis by regulation of IL-6 signal transduction

Research Project

Project/Area Number 14370163
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 内科学一般
Research InstitutionOsaka University

Principal Investigator

NISHIMOTO Norihiro  Osaka University, Osaka University, Frontier Biosciences, Professor (80273663)

Co-Investigator(Kenkyū-buntansha) YOSHIZAKI Kazuyuki  Osaka University, Health and Sports Science, Professor (90144485)
SUGIMURA Kazuhisa  Kagoshima University, Faculty of Engineering, Professor (80127240)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥13,700,000 (Direct Cost: ¥13,700,000)
Fiscal Year 2003: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2002: ¥9,500,000 (Direct Cost: ¥9,500,000)
Keywordsrheumatoid arthritis / interleukin-6 / humanized anti-IL-6 receptor antibody / vascular endothelial growth factor / adenoviral vector / SOCS-1 / negative regulator / アデノウイルスベクター / SSI-1
Research Abstract

Interleukine 6 (IL-6) is one of the inflammatory active indexes in rheumatoid arthritis (RA) patients. A massive clinical trial using a humanized anti-IL-6 receptor antibody (MRA), involving 29 institutes under the organization of Osaka University, has provedn that IL-6 signal blocking by MRA is an efficacious treatment for RA. We have also verified two critical mechanisms for the anti-IL-6 receptor therapy. One is anti-angiogenic activity in synoviocytes by means of the inhibition of IL-6-induced vascular endothelial growth factor (VEGF) production, and the other is preventing the destruction of bone and cartilage by inhibiting IL-6-induced matrix metalloproteinase (MMP) over-production. We have found that IL-6, synergistically with IL-1 and TNF α, up-regulates VEGF and MMP production and therefore plays a pivotal role. The anti-IL-6 treatment appeared most efficacious for the suppression of VEGF and MMP in RA patients. Augmentation of VEGF production induced by IL-6 was observed in n … More ormal fibroblasts, synovial fibroblasts obtained from OA patients as well as RA. We also found that IL-6 induced VEGF production in malignant mesothelioma cells.
We established secondary amyloidosis mouse models by virtue of the administration of amyloid enhancing factor (AEF) to the IL-6 transgenic mouse. The treatment of an anti-mouse IL-6 receptor antibody mitigated the amyloidosis in these mouse models, which means that IL-6 is an essential molecule for the development of secondary amyloidosis.
SOCS1 and SOCS3, negative regulators of IL-6 cytokine signal, are available for the therapeutic agents as anti-IL-6 therapy. We evaluated optimal gene transfer conditions to achieve the effective expression of SOCS. Although the adenovirus has shown low infectivity to fibroblasts, infectivity enhanced adenoviruses having RGD motifs in their fiber region acquired high infectivity to the synovial fibroblasts and overcame this disadvantage. We also replaced the universal promoter (CMV) with inflammation specific promoters for the control of the transgene expression in RA synovial fibroblasts.
We generated a single chain recombinant antibody comprising human IgG1 Fc genetically fused to a single chain Fv derived from the parent antibody MRA. This molecule successfully reduced the IL-6-dependent cell growth and inhibited the phosphorylation of STAT3 induced by IL6 stimulation. This therapeutic agent, encoded on single gene, is easily applicable to the viral gene transfer method. This molecule should be a potential device for the anti-IL-6 therapy combined with the gene therapy method. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (34 results)

All 2004 2003 2002 Other

All Journal Article (18 results) Book (2 results) Publications (14 results)

  • [Journal Article] A Pilot Randomized Trial of a Human Anti-Interleukin-6 Receptor Monoclonal Antibody in Active Crohn's Disease. Gastroenterol.2004

    • Author(s)
      Ito H, et al.
    • Journal Title

      Gastroenterol. 126

      Pages: 989-996

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Treatment of rheumatoid arthritis with humanized anti-interleukin 6 receptor antibody.2004

    • Author(s)
      Nishimoto N, et al.
    • Journal Title

      Arthritis Rheum. 50

      Pages: 1761-69

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Anti-interleukin-6 receptor antibody inhibits murine AA-amyloidosis.2004

    • Author(s)
      Mihara M, et al.
    • Journal Title

      J Rheumatol. 31

      Pages: 1132-8

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Inhibition of IL-6 for the treatment of inflammatory diseases.2004

    • Author(s)
      Nishimoto N, et al.
    • Journal Title

      Curr Opin Pharmacol. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Effect of anti-mouse interleukin-6 receptor antibody in autoimmune mouse models.2004

    • Author(s)
      Mihara M, et al.
    • Journal Title

      Prog in Monocl Antibody Res. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Adult Still's disease reflects a Th1 but rather a Th2 cytokineprofile.2004

    • Author(s)
      Saiki O, et al.
    • Journal Title

      Clin Immunol. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Humanized anri-interleukin-6 receptor antibody induced long-term remission in a patient with life-threatening refractory autoimmune hemolytic anemia.2004

    • Author(s)
      Kunitomi A, et al.
    • Journal Title

      Int J of Hematol. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] A Pilot Randomized Trial of a Human Anti-Interleukin-6 Receptor Monoclonal Antibody in Active Crohn's Disease.2004

    • Author(s)
      Ito H, et al.
    • Journal Title

      Gastroenterol. 126

      Pages: 989-996

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Anti-interleukin-6 receptor antibody inhibits murine AA-amyloidosis.2004

    • Author(s)
      Mihara M, et al.
    • Journal Title

      J Rheumatol 31

      Pages: 1132-8

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Effect of anti-mouse interleukin-6 receptor antibody in autoimmune mouse models.2004

    • Author(s)
      Mihara M, et al.
    • Journal Title

      Progin Monocl Antibody Res. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Adult Still's disease reflects not a Th1 but rather a Th2 cytokine profile.2004

    • Author(s)
      Saiki O, et al.
    • Journal Title

      Clin Immunol (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Humanized anti-interleukin-6 receptor antibody induced long-term remission in a patient with life-threatening refractory autoimmune hemolytic anemia.2004

    • Author(s)
      Kunitomi A, et al.
    • Journal Title

      Int J of Hematol (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Sustained interleukin-6 signaling leads to the development of lymphoid organ-like structures in the lung.2003

    • Author(s)
      Goya S, et al.
    • Journal Title

      J Pathol. 200

      Pages: 82-87

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Anti-interleukin-6 receptor antibody therapy reduces vascular endotherlial growth factor (VEGF) production in rheumatoid arthritis.2003

    • Author(s)
      Nakahara H, et al.
    • Journal Title

      Arthritis Rheum. 48

      Pages: 521-529

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Enhanced production of osteopontin in multiple myeloma : clinical and pathogenic implications.2003

    • Author(s)
      Saeki Y, et al.
    • Journal Title

      Br J Haematol. 123

      Pages: 263-270

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Toxicity, pharmacokinetics, and dose finding study of repetitive treatment with humanized anti-interleukin 6 receptor antibody, MRA, in rheumatoid arthritis -a phase I/II clinical study of MRA for rheumatoid arthritis in Japan2003

    • Author(s)
      Nishimoto N, et al.
    • Journal Title

      J Rheumatol. 30

      Pages: 1426-1435

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-Interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study.2003

    • Author(s)
      Nishimoto N, et al.
    • Journal Title

      J Rheumatol 30

      Pages: 1426-1435

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Enhanced production of osteopontin in multiple myeloma : clinical and pathogenic implications.2003

    • Author(s)
      Saeki Y, et al.
    • Journal Title

      Br J Haematol 123

      Pages: 263-270

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Book] アレルギー・リウマチ膠原病の最新医療2003

    • Author(s)
      西本憲弘
    • Total Pages
      473
    • Publisher
      寺田国際事務所/先端医療技術研究所
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Book] Targeted Therapies in Rheumatology2002

    • Author(s)
      Nishimoto N, et al.
    • Total Pages
      768
    • Publisher
      Taylor & Francis, A Martin Dunitz Book
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Goya S, et al.: "Sustained interleukin-6 signaling leads to the development of lymphoid organ-like structures in the lung"J.Pathol. 200. 82-87 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakahara H, et al.: "Anti-interleukin-6 receptor antibody therapy reduces vascular endotherlial growth factor (VEGF) production in rheumatoid arthritis"Arthritis Rheum.. 48. 521-529 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Saeki Y, et al.: "Enhanced production of osteopontin in multiple myeloma : clinical and pathogenic implications"Br J Haematol.. 123. 263-270 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nishimoto N, et al.: "Toxicity, Pharmacokinetics, and dose finding study of repetitive treatment with humanized anti-interleukin 6 receptor antibody, MRA, in rheumatoid arthritis -a phase I/II clinical study of MRA for rheumatoid arthritis in Japan-"J.Rheum.. 30. 1426-1435 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ito H, et al.: "A Pilot Randomized Trial of a Human Anti-Interleukin-6 Receptor Monoclonal Antibody in Active Crohn's Disease. Gastroenterol."Gastroenterol.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mihara M, et al.: "Anti-interleukin-6 receptor antibody inhibits murine AA-amyloidosis"J.Rheum.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nishimoto N, et al.: "Treatment of rheumatoid arthritis with humanized anti-interleukin 6 receptor antibody"Arthritis Rheum.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Okazaki M, et al.: "Characterization of anti-mouse Il-6 receptor antibody"Immunol. Lett.. 84. 231-240 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mihara M, et al.: "Influences of Anti-mouse IL-6 receptor antibody on immune responses in mice"Immunol. Lett.. 84. 223-229 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Choy EH, et al.: "Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin 6 receptor monoclonal antibody in rheumatoid arthritis : a randomized, double-blind, placebo-controlled, dose-escalation trial"Arthritis Rheum. 46. 3143-3150 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iwamoto M, et al.: "Humanized monoclonal anti-interleukin 6 receptor antibody for treatment of intractable adult-onset Still's disease"Arthritis Rheum. 46. 3388-3389 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nishimoto N, et al.: "Toxicity, pharmacokinetics, and dose finding study of repetitive treatment with humanized anti-interleukin 6 receptor antibody, MRA, in rheumatoid arthritis ; a phase I/II clinical study of MRA for rheumaoid arthritis in Japan"J. Rheum. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakahara H, et al.: "Anti-interleukin-6 receptor antibody therapy reduces vascular endotherial growth factor(VEGF)production in rheumatoid arthritis"Arthritis Rheum. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nishimoto N, et al.: "Targetted therapy in rheumatology"Martin Duniz, London. 10 (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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