Molecular and immunological study on the pathogenesis of hepatitis C

丙型肝炎发病机制的分子和免疫学研究

• 批准号: 07407015
• 负责人: IMAWARI Michio
• 金额: $ 8.13万
• 依托单位: Jichi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07407015/
• 关键词: hepatitis C; hepatitis C virus; cytotoxic T lymphocyte; HLA B44; epitope; perforin; Fas; TNF; ヘルパーT細胞; インターフェロンγ; インターロイキン4; 変異; パ-フォリン

In the present study, we demonstrated that HLA B44-positive hepatitis C patients with demonstarable CTL response to HCV core antigen a.a. 88-96 had lower levels of serum HCV RNA, suggesting that CTL may suppress the outgrowth of HCV.In addition, CTh response was observed to multiple HCV epitopes in the same patients. Thus CTL response to HCV infection is not strong enough to eliminate the virus.The variation of amino acid in HCV core a. a. 88-96 was observed only 3 of 27 HLA B44-positive patients. All three variants could be recognized by CTL as effectively as wild-type HCV antigen, but two of three variants could not induce CTL effectively while the other one could induce CTL.Furthermore, when a small amount of variant HCV co-existed with wild-type HCV, the induction of CTL recognizing spesifically variant epitope was sppressed.HCV-specific CTL recognized and killed HCV-infected target cells by perform-, Fas ligand-, and. TNF-based mechanisms. In addition, activated CTL killed bystander sensitive non-infected cells by Fas ligand and TNF-based mechanisms. The mechanisms may contribute to the expansion of inflammation in the liver.

在本研究中，我们证明了HLA b44阳性的丙型肝炎患者对HCV核心抗原a.a.88 -96有明显的CTL反应，血清HCV RNA水平较低，表明CTL可能抑制HCV的生长。此外，在同一患者中观察到对多个HCV表位的CTh反应。因此，CTL对HCV感染的反应不足以消除病毒。HLA b44阳性27例患者中，仅3例出现氨基酸变异。这三种变体均能像野生型HCV抗原一样被CTL有效识别，但其中两种变体不能有效诱导CTL，而另一种变体能诱导CTL。此外，当少量变异型HCV与野生型HCV共存时，识别特异性变异表位的CTL的诱导被抑制。hcv特异性CTL识别和杀死hcv感染的靶细胞通过执行-，Fas配体-和。TNF-based机制。此外，激活的CTL通过Fas配体和基于tnf的机制杀死旁观者敏感的非感染细胞。这种机制可能导致肝脏炎症的扩大。

项目成果

Ando,Kazuki: "Perforin,Fas/Fas Ligand,TNF-α pathways as specific and bystander killing mechanisms of hepatitis C virus-specific human CTL" Journal of Immunology. 158. 5283-5291 (1997)

Ando，Kazuki：“穿孔素、Fas/Fas 配体、TNF-α 途径作为丙型肝炎病毒特异性人类 CTL 的特异性和旁观者杀伤机制”《免疫学杂志》158. 5283-5291 (1997)。

Ando, Kazuki: "Perforin, Fas/Fas ligand, TNF-α pathways as specific and bystander killing mechanisms of hepatitis C virus-specific human CTL" Journal of Immunology. 5283-5291 (1997)

Ando, Kazuki：“穿孔素、Fas/Fas 配体、TNF-α 途径作为丙型肝炎病毒特异性人类 CTL 的特异性和旁观者杀伤机制”《免疫学杂志》5283-5291 (1997)。

Kita, Hiroto: "A minimal and optimul cytotoxic T cell epitope within hepatitis C virus nucleoprotein" Jpurnal of General Virology. 76. 3189-3193 (1995)

Kita, Hiroto：“丙型肝炎病毒核蛋白内的最小且最佳的细胞毒性 T 细胞表位”《普通病毒学杂志》。

Kaneko, Takashi.: "Impaired induction of cytotoxic T lymphocytes by antagonis of a weal agonist borne by a variant hepatitis C virus epitope" European Journal of Immunology. 27. 1782-1787 (1997)

Kaneko, Takashi.：“丙型肝炎病毒变异表位所携带的 Weal 激动剂的拮抗作用对细胞毒性 T 淋巴细胞的诱导作用受损”《欧洲免疫学杂志》。

Imawari, Michio: "Th1 and Th2 imbalance in chronic hepatitis C" Journal of Gastroenterology. 33. 602-603 (1998)

Imawari, Michio：“慢性丙型肝炎中 Th1 和 Th2 失衡”胃肠病学杂志。