| Project/Area Number |
15590697
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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 |
Gastroenterology
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| Research Institution | Aichi Medical University School of Medicine |
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Principal Investigator |
ISHIKAWA Tetsuya Aichi Medical University, School of Medicine, Lecturer, 医学部, 講師 (10288508)
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| Co-Investigator(Kenkyū-buntansha) |
KAKUMU Shinichi Aichi Medical University, School of Medicine, Professor, 医学部, 教授 (10115545)
OKUMURA Akihiko Aichi Medical University, School of Medicine, Lecturer, 医学部, 講師 (70288512)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2003: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | HBV / transgenic mouse / CTL / knock-out mouse / TNF-α / NKT / B型肝炎ウイルス / 細胞傷害性Tリンパ球 / DNAマイクロアレイ |
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| Research Abstract |
Adoptive transfer of HBs-specific CTL clones into HBV-transgenic mice (HBV-Tg) causes acute or fluminant hepatitis in those mice. Using this model, we investigated the mechanism and the pathogenesis of immune-mediated hepatitis. The magnitude of hepatitis differed and sometimes showed more than ten times difference depending on the CTL clones used for the transfer. The differences in the disease by the individual CTL clones did not depend on the amount of the cytokines, such as TNF-α and IFN-γ, produced by the CTL clones. The disease magnitude might be determined by other functions of CTL clone, the extent of host effector cell activation, or unknown host factors affected by the CTL administration. To explore these possibilities, we established HBV-Tg with TNF-α gene knockout (HBV-Tg/TNF-α KO), and HBV-Tg with Jα281 gene knockout (HBV-Tg/NKT KO), and analyzed the roles of TNF-α and NKT cells for the disease pathogenesis. The disease magnitude dramatically declined in HBV-Tg/TNF-α KO compared to that in HBV-Tg, showing the decrease of peak transaminase levels less than one twentieth of those in HBV-Tg. The cell population responsible for TNF-α production, the factors that regulate TNF-α, and influence of TNF-α for the expression of other host genes, are currently under investigation. On the other hand, the peak transaminase levels were significantly raised in HBV-Tg/NKT KO compared to those in HBV-Tg. The expression of IL-10 was upregulated in hepatic NKT cells of HBV-Tg as early as 3 hours after CTL administration. These results may suggest that NKT cells suppress the expressive exacerbation of hepatitis through IL-10 production. Various immune cells as well as cytokine play multilateral roles on disease pathogenesis of hepatitis. The detailed analyses for these players are necessary to explore the possibilities of novel therapy for hepatitis, which aims the specific reduction of inflammation and the promotion of liver regeneration.
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