| Project/Area Number |
08457167
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Osaka University |
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Principal Investigator |
HAYASHI Norio Osaka University Medical School, Associate Professor, 医学部, 助教授 (00144478)
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| Co-Investigator(Kenkyū-buntansha) |
KANTO Tatsuya Osaka University Hospital, Medical Staff, 医学部・附属病院, 医員
MITA Eiji Osaka University Hospital, Medical Staff, 医学部・附属病院, 医員
TAKEHARA Tetsuo Osaka University Hospital, Medical Staff, 医学部・附属病院, 医員
KASAHARA Akinori Osaka University Hospital, Associate Professor, 医学部・附属病院, 助教授 (70214286)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 1997: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1996: ¥5,700,000 (Direct Cost: ¥5,700,000)
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| Keywords | Hepatitis C Virus / Apoptosis / Fas Antigen / Soluble Fas Antigen / B7-1 (CD80) / Cytotoxic T Lymphocyte / HLA / TGF-beta1 / リボザイム / TGF-α1 / C型肝炎ウイルス / 遺伝子導入 / セカンドシグナル / B7-1遺伝子 / B7-2遺伝子 / HLAクラスI / インターフェロン |
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| Research Abstract |
Cytotoxic T lymphocytes (CTL) play an important role in liver cell injury by hepatitis C virus (HCV) infection. We demonstrated that liver-infiltrating CD8 positive lymphocytes and natural killer cells expressed the functional Fas ligand. On the other hand, B7/BB-1 was strongly expressed in the cytoplasm of hepatocytes of HCV-infected liver. B7/BB-1-positive cells accompanied liver-infiltrating lymphocytes and were detected near HCV core antigen-and HLA class I-positive cells. B7/BB-1 expression was closely correlated with the activity of viral hepatitis. These findings suggest that B7/BB-1 expression by hepatocytes may be induced by HCV infection and may trigger generation and activation of CTL,which may cause damage to HCV-infected HLA class I-expressing hepatocytes via Fas antigen.
We measured the serum level of soluble Fas antigen (sFas) in patients with chronic hepatitis C and healthy volunteers. The serum sFas level was significantly higher in chronic hepatitis C patients than in
… More
healthy volunteers. It was also correlated with the expression level of Fas in hepatocytes and the severity of liver inflammation. Thus it may serve as a novel indicator for the activity of liver inflammation.
When HLA typing was tested among HCV-infected individuals, extended haplotypes including class I B54 are closely associated with the progression of liver injury, whereas extended haplotypes including class II DRB1^*1302-DQB1^*0604 are associated with low hepatitis activity. Thus the host factors as well as viral factors may determine the activity of CTL.
We showed that endogeneous TGF-beta1 block the induction of HCV-specific CTL and their cytolytic activity. By exvivo cell system, we demonstrated that the appropriate does of IL-2 and addition of anti-TGF-beta1 can induce the high cytotoxicity of CTL.The high activity was also introduced by using dendritic cells as antigen-presenting cells.
In summary, cytotoxic activity of CTL via Fas system plays a dominat role in liver cell damage by HCV infection. Some cytokines such as TGF-beta1 can modulate the CTL activity and regulate liver apoptosis. Less
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