IL-27调控Th17细胞分化抑制原发性胆汁性肝硬化进展的研究

原发性胆汁性肝硬化(PBC)是一种胆汁淤积性自身免疫性肝病，易渐进发展为肝纤维化、肝硬化和肝衰竭。PBC进展异质性大，病情监测困难。我们前期研究证实PBC自身免疫反应主要由Th17细胞介导，IL-27是Th17细胞的主要调控因子。研究肺纤维化小鼠模型证实IL-27可以抑制成纤维细胞功能。为进一步阐明IL-27对Th17调控在PBC进程中的作用和机制，本项目拟检测PBC患者和小鼠外周血/肝中IL-27、Th17细胞、相关细胞因子水平以及IL-27、IL-27受体在肝组织的定位及表达，观察IL-27、IL-27抗体干预前后对Th17细胞分化及JAK/STAT、TGF-β/Smad信号通路的影响，从炎症和免疫调节的角度分析IL-27调控Th17与临床指标、病理分期及疗效的关系，阐明IL-27调节PBC免疫功能失衡抑制PBC进程的分子机制，为PBC病情评估、病程监测及疗效监控发现潜在的分子标志物。

Primary biliary cirrhosis (PBC) is a chronic intrahepatic cholestatic autoimmune liver desease that can evolve into hepatic fibrosis, hepatic cirrhosis and hepatic failure. But the progression of PBC is heterogeneous. Nowadays,there is no good method to monitor disease progression. Our previous studies demonstrates that Th17 cells are the key immunal effector cells of PBC . The increased Th17 cells can lead to the occurrence of disease and liver fibrosis. IL-27 can inhibited fibrosis disease through regulating the Th17 cells differentiation. In this research, we use flow cytometric analysis to examined the lever of IL-27、 Th17 cells and related cytokines in peripheral blood and hepatic tissue.To clarify the expression,location,cell origin of IL-27 in PBC, we perform Immunohistochemical staining and RT-PCR.To observe the role of the IL-27 regulating Th17 differentiation and secretory function,spleen lymphocytes will be co-cultured with IL-27and anti-IL-27 in vitro. We use Western Blotting to explore the role of JAK / STAT signaling pathway in IL -27 regulating function. To further investigate the role of IL-27 in the pathological processes of PBC,the correlation between IL-27 expression and disease activity, including biologychemystry and Mayo score will be analyzed. The research will further elucidate the molecular mechanism of IL-27 inhibit liver fibrosis in PBC and provide a new biomarker and target for monitoring、prevention and treatment of PBC.