2004 Fiscal Year Final Research Report Summary
Development of adeno-associated virus vector-mediated IL-4 gene delivery system for rheumatoid arthritis
| Project/Area Number |
15591570
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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 |
Orthopaedic surgery
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| Research Institution | Toyama Medical and Pharmaceutical University |
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Principal Investigator |
SUGIYAMA Fiji Toyama Medical and Pharmaceutical University, Medicine, Associate Professor, 医学部, 助教授 (70179167)
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| Co-Investigator(Kenkyū-buntansha) |
KISHI Hiroyuki Toyama Medical and Pharmaceutical University, Immunology, Associate professor, 医学部, 助教授 (60186210)
MURAGUCHI Atsushi Toyama Medical and Pharmaceutical University, Immunology, Professor, 医学部, 教授 (20174287)
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| Project Period (FY) |
2003 – 2004
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| Keywords | interleukin-4 / osteoclast / gene therapy / adeno-associated virus / rheumatoid arthritis |
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| Research Abstract |
Bone-resorbing osteoclasts play important roles in joint destruction in rheumatoid arthritis(RA). Since IL-4, an anti-inflammatory cytokine, is capable of inhibiting osteoclast generation, the expression of IL-4 in rheumatoid synovium would be a promising applicant for the treatment of RA. In this study we examined the effect of IL-4 gene delivery using adeno-associated virus on RANKL-stimulated osteoclast generation in human peripheral blood monocytes. First, we developed recombinant adeno-associated virus(AAV) vector containing human cDNA for IL-4(AAV IL-4). The AAV IL-4 efficiently transduced human monocytes, and induced the cells to produce large amounts of IL-4. However, the AAV-IL-4 did not transduce peripheral T cells and B cells as well. RANKL, an osteoclast differential factor, induced osteoclast generation from peripheral monocytes in the presence of M-CSF. Transduction of AAV IL-4 potently inhibited the generation of osteoclasts, suggesting that IL-4 gene therapy is effective for joint destruction in RA. In addition, we evaluated the effect of IL-4 on intracellular signaling during RANKL-mediated osteoclast generation in murine bone mallow cells. We demonstrated that IL-4 inhibited osteoclast generation via inhibition of transcription factors, c-Fos and NFATc1. These data provide new insight in development of new treatment for RA.
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