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

丙型肝炎病毒（HCV）感染经常持续，发展为慢性肝炎和肝硬化，最后发展为肝细胞癌。尽管感染细胞中的病毒被病毒特异性细胞毒性T淋巴细胞（CTL）消灭，CTL识别内源性合成的、经过处理的由HLA呈递的病毒蛋白并裂解细胞，但CTL反应是由辅助T细胞和免疫调节细胞因子调节的。在本研究中，我们主要研究慢性HCV感染患者外周血蚂蚁肝组织中辅助性T细胞和免疫调节细胞因子的反应。在慢性HCV感染中，产生干扰素-γ的1型辅助性T细胞应答HCV蛋白主导了产生白细胞介素-4的2型辅助性T细胞应答。然而，HCV蛋白刺激免疫抑制性白细胞介素-10的产生。在慢性丙型肝炎患者外周血中，hcv刺激下产生白细胞介素-10的细胞数量大于hcv刺激下产生干扰素-γ的细胞数量。因此，抗hcv反应似乎在外周血中被抑制。hcv特异性辅助性T细胞集中在肝组织中。外周血中受HCV刺激产生干扰素γ的细胞数量与血清HCV RNA水平呈负相关。干扰素治疗在3个月时降低了hcv刺激的外周血产生干扰素γ的细胞数量，但随后又恢复到治疗前的水平。慢性丙型肝炎病毒感染患者外周血单个核细胞刺激干扰素-γ和白细胞介素-10产生的HCV蛋白中普遍存在区域。最后，我们在HCV中发现了一个与HLA-A^*0206相关的ctl识别的表位。

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.