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

丙型肝炎病毒（HCV）感染经常持续存在，进展为慢性肝炎和肝硬化，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细胞毒性T淋巴细胞（CTL）清除，所述细胞毒性T淋巴细胞识别由HLA呈递的内源性合成、加工的病毒蛋白并裂解细胞，但CTL应答由辅助T细胞和免疫调节细胞因子调节。在本研究中，我们主要研究了慢性HCV感染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HCV感染中，1型辅助性T细胞应答产生干扰素-γ，以应答HCV蛋白为主，2型辅助性T细胞应答产生白细胞介素-4。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刺激的白细胞介素-10产生细胞的数量大于HCV刺激的γ-干扰素产生细胞的数量。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HCV刺激的γ-干扰素产生细胞的数量与血清HCV RNA水平呈负相关。干扰素治疗3个月后，外周血HCV刺激的γ-干扰素产生细胞数下降，但随后恢复到治疗前水平。HCV蛋白中存在刺激慢性HCV感染者外周血单个核细胞产生IFN-γ和IL-10的区域。最后，我们鉴定了HCV中与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.