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Therapeutic approach to hepatitis C by regulation of apoptosis-related gene

调控凋亡相关基因治疗丙型肝炎

基本信息

批准号：
08457167
负责人：
HAYASHI Norio
金额：
$ 5.57万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457167/
关键词：
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

项目摘要

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

细胞毒性T淋巴细胞（CTL）在丙型肝炎病毒（HCV）感染肝细胞损伤中起重要作用。我们证实肝脏浸润性CD8阳性淋巴细胞和自然杀伤细胞表达功能性Fas配体。另一方面，B7/BB-1在hcv感染肝脏的肝细胞细胞质中强烈表达。B7/ bb -1阳性细胞伴肝脏浸润淋巴细胞，并在HCV核心抗原和HLA i类阳性细胞附近检测到。B7/BB-1的表达与病毒性肝炎的活动密切相关。这些发现表明，HCV感染可能诱导肝细胞表达B7/BB-1，并可能触发CTL的产生和激活，CTL可能通过Fas抗原对HCV感染的HLA -i类表达肝细胞造成损伤。我们测量了慢性丙型肝炎患者和健康志愿者的血清可溶性Fas抗原（sFas）水平。慢性丙型肝炎患者血清sFas水平明显高于健康志愿者。与肝细胞Fas表达水平及肝脏炎症程度相关。因此，它可以作为肝脏炎症活动的新指标。当在hcv感染者中进行HLA分型测试时，包括I类B54在内的扩展单倍型与肝损伤的进展密切相关，而包括II类DRB1^*1302-DQB1^*0604在内的扩展单倍型与低肝炎活性相关。因此，宿主因子和病毒因子都可能决定CTL的活性。我们发现内源性tgf - β 1阻断了hcv特异性CTL的诱导及其细胞溶解活性。通过体外细胞系统，我们证明了适当的IL-2和抗tgf - β 1的加入可以诱导CTL的高细胞毒性。利用树突状细胞作为抗原提呈细胞，也引入了高活性。综上所述，CTL通过Fas系统的细胞毒活性在HCV感染引起的肝细胞损伤中起主导作用。一些细胞因子如tgf - β 1可调节CTL活性，调控肝细胞凋亡。少