Investigating the pathogenic role and its novel intervention of virus-associated double-stranded RNA in asthma
| Project/Area Number |
18591114
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | Kyushu University |
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Principal Investigator |
MATSUMOTO Koichiro Kyushu University, Hospital, Lecturer (60325462)
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| Co-Investigator(Kenkyū-buntansha) |
INOUE Hiromasa Kyushu University, Graduate School of Medical Scineces, Associate Professor (30264039)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| 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)
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| Keywords | virus / bronchial asthma / allergy / double-stranded RNA / IL-13 / IL-10 / regulatory T-cell / mast cell |
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| 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
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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
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Report
(3 results)
Research Products
(4 results)
