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Analysis of cellular immune responses in perihperal blood and liver tissues in HCV infection

HCV感染后外周血和肝组织细胞免疫反应分析

基本信息

批准号：
11470136
负责人：
IMAWARI Michio
金额：
$ 3.01万
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 (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470136/
关键词：
hepatitis C virus immunology helper T cell cytotoxic T lymphocyte interferon-γ interleukin-4 interleukin-10 ELISpot C型肝炎 HCV抗原 C型肝炎ウイルスコア蛋白 C型肝炎ウイルスNS3蛋白

项目摘要

Hepatitis C virus (HCV) infection frequently persists, progresses to chronic hepatitis and cirrhosis, and finally develops hepatocellular carcinoma. Although viruses in the infected cells are eliminated by virus-specific cytotoxic T lymphocytes (CTLs) that recognize endogenously synthesized, processed viral proteins presented by HLA and lyse the cells, the CTL responses are regulated by helper T cells and immunomodulatory cytokines. In the present study, we investigated mainly the helper T cell and immunomodulatory cytokine responses in peripheral blood ant liver tissues of patients with chronic HCV infection. In chronic HCV infection, type 1 helper T cell responses that produced interferon-γin response to HCV proteins dominated type 2 helper T cell responses that produced interleukin-4. However, HCV proteins stimulated the production of immunosuppressive interleukin-10. In the peripheral blood of patients with chronic hepatitis C, the number of HCV-stimulated interleukin-10-producing cells was larger than that of HCV-stimulated interferon-γ-producing cells. Thus, the anti-HCV responses seemed to be suppressed in the peripheral blood. HCV-specific helper T cells were concentrated in the liver tissues. The number of HCV-stimulated interferon-γ-producing cells in the peripheral blood was inversely correlated with serum HCV RNA levels. Interferon treatment decreased the number of peripheral blood HCV-stimulated interferon-γ-producing cells at 3 month, but the number returned to the pretreatment level later. There were regions in HCV proteins that stimulated of production of interferon-γ and interleukin-10 by peripheral blood mononuclear cells of patients with chronic HCV infection in common. Finally we identified an epitope in HCV recognized by CTLs in association with HLA-A^*0206.

丙型肝炎病毒(HCV)感染经常持续，进展为慢性肝炎和肝硬变，最终发展为肝细胞癌。尽管感染细胞中的病毒被病毒特异性的细胞毒性T淋巴细胞(CTL)清除，CTL识别内源性合成的、加工过的病毒蛋白并溶解细胞，但CTL反应受到辅助T细胞和免疫调节细胞因子的调节。本研究主要探讨慢性丙型肝炎患者外周血和肝组织中辅助性T细胞和免疫调节细胞因子的反应。在慢性丙型肝炎病毒感染中，对丙型肝炎病毒蛋白产生干扰素-γ的1型辅助T细胞反应主导产生白细胞介素4的2型辅助T细胞反应。然而，丙型肝炎病毒蛋白刺激免疫抑制白介素10的产生。慢性丙型肝炎患者外周血中丙型肝炎病毒刺激的IL-10产生细胞数量多于丙型肝炎病毒刺激的干扰素γ产生细胞。因此，抗丙型肝炎病毒的反应似乎在外周血液中受到抑制。丙型肝炎病毒特异性辅助性T细胞主要集中在肝组织中。外周血中丙型肝炎病毒刺激的干扰素-γ产生细胞的数量与血清丙型肝炎病毒RNA水平呈负相关。干扰素治疗3个月后外周血中丙型肝炎病毒刺激的干扰素-γ产生细胞数量减少，但随后恢复到治疗前水平。慢性丙型肝炎患者外周血单核细胞产生干扰素-γ和白介素10的过程中，普遍存在丙型肝炎病毒蛋白中刺激干扰素-DNA和白介素10的区域。最后，我们确定了丙型肝炎病毒中与人类白细胞抗原A^*0206相关的CTL识别的表位。