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Investigating the pathogenic role and its novel intervention of virus-associated double-stranded RNA in asthma

Research Project

Project/Area Number 18591114
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 膠原病・アレルギー・感染症内科学
Research InstitutionKyushu University

Principal Investigator

MATSUMOTO Koichiro  Kyushu University, Hospital, Lecturer (60325462)

Co-Investigator(Kenkyū-buntansha) INOUE Hiromasa  Kyushu University, Graduate School of Medical Scineces, Associate Professor (30264039)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,860,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥360,000)
Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
Keywordsvirus / bronchial asthma / allergy / double-stranded RNA / IL-13 / IL-10 / regulatory T-cell / mast cell
Research Abstract

Despite a therapeutic improvement, there has been considerable number of newly diagnosed patients of allergic asthma. Such pathogenesis is frequently associated with viral infection. Many viruses causing airway infection have single-stranded RNA as their own genome and then generate double-stranded RNA (dsRNA), as intermediates for replication. Hence, it is rational approach to target dsRNA for elucidating the mechanisms of virus-associated pathogenesis of asthma. Recent progress in molecular immunology revealed that dsRNA induces strong innate immune responses. Those temporal responses may affect the ongoing acquired immune responses, including allergic sensitization. To elucidate the role of dsRNA on the development of asthma, we examined whether treatment of polyinocinic polycytidilic acid (poly IC), a synthetic mimetic of viral dsRNA, during allergen sensitization affects or not the following asthma phenotype. When poly IC was administered at every sensitization with OVA, the eosin … More ophilia in BALF and the airway hyperresponsiveness after OVA inhalation challenge were augmented in comparison with those of saline-treated mice. This augmentation required simultaneous and repeated administration of poly IC with OVA sensitization, suggesting that poly IC may affect the process of sensitization. The concentration of IL-13 in BALF after OVA challenge in poly IC-treated mice was selectively higher than that in saline-treated mice. When an IL-13 inhibitor was administered before every OVA challenge, no augmentation of asthma phenotype was found. Flow cytometric analysis of OVA-challenged lung cells revealed that CD8^+T-cell subs et was a major source of over-produced IL-13. Thus, the selective over-production of IL-13 from CD8^+T-cell subset may be crucial for the augmented phenotype of asthma induced by poly IC treatment. Interestingly, these phenotypes were mast cell-dependent since the augmented phenotype of asthma was not induced in mast cell-deficient mice but done in the mice pretreated with mast cell-transfer before poly IC treatment. When poly IC was administered with D-galactosamine (D-gal), the augmented phenotype of asthma accompanied with the down-regulation of production of IL-10 and IFN-gamma. The Foxp3+regulatory T cells also decreased in the lungs of allergen-exposed mice. The poly IC/D-gal-induced augmentation of asthma phenotype was not induced in the mice pretreated with anti-IL-10 receptor antibody, but done in IFN-gamma-deficient mice. These results suggest that double-stranded RNA may enhance the induction of asthma phenotype by multiple mechanisms including mast cell/CD8+T-cell/IL-13 pathway and regulatory T-cell/IL-10 pathway. Less

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (4 results)

All 2007 2006

All Presentation (4 results)

  • [Presentation] Effect of double-stranded RNA on the pathogenesis of allergic asthma2007

    • Author(s)
      松元 幸一郎
    • Organizer
      第37回日本免疫学会学術集会
    • Place of Presentation
      グランドプリンスホテル新高輪
    • Year and Date
      2007-11-20
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] アレルギー性喘息の発症に対する2本鎖RNAの影響についての検討2007

    • Author(s)
      松元 幸一郎
    • Organizer
      日本免疫学会学術集会
    • Place of Presentation
      東京都(グランドプリンスホテル新高輪)
    • Year and Date
      2007-11-20
    • Related Report
      2007 Annual Research Report
  • [Presentation] マウス喘息モデルを用いたウィルス関連分子2本鎖RNAによる喘息反応増強のメカニズムの解明2007

    • Author(s)
      松元 幸一郎
    • Organizer
      第47回日本呼吸器学会総会
    • Place of Presentation
      東京国際フォーラム
    • Year and Date
      2007-05-10
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] マウス喘息モデルにおいて感作時の2本鎖RNA投与はIL-13産生亢進を介して喘息反応を増強する2006

    • Author(s)
      松元 幸一郎
    • Organizer
      第46回日本呼吸器学会総会
    • Place of Presentation
      東京国際フォーラム
    • Year and Date
      2006-06-02
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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