炎性细胞因子，免疫细胞和造血干细胞在原发性胆汁性肝硬化（PBC）免疫失衡中的机制探究

原发性胆汁性肝硬化（PBC）是一种由于免疫系统攻击自身肝脏而引发的慢性肝脏疾病。该疾病的重要特征是肝脏中免疫平衡失调：大量的炎性细胞浸润以及Th1型细胞因子水平升高。该疾病的病因和发病机理尚不清楚，接受肝脏移植的PBC病人也有很高的复发率，因此现阶段缺乏有效的治疗手段。本项目将利用自发自身免疫性肝病并发展为肝脏纤维化的小鼠模型对PBC中免疫失衡的机制进行深入研究，具体内容如下：1）明确Th1型免疫反应失衡在PBC样肝脏炎症及纤维化中的作用机制；2）探究模型鼠肝脏组织特异性的T细胞在PBC样疾病中的致病机制；3）探索PBC模型鼠中造血干细胞表型异常的原因和免疫失衡中造血干细胞功能。本项目以PBC模型鼠为研究平台，探讨炎性细胞因子，炎性灶驻留致病性细胞，以及造血系统整体调控在自身免疫肝病发生过程中的作用，揭示免疫失衡的细胞分子学机制，为阐明自身免疫肝病的发病机理及制定有效治疗方案提供理论依据。

Primary biliary cirrhosis (PBC) is a chronic liver disease caused by progressively immune-mediated liver injury. This disease is characterized by disorder of immune balance, as increased infiltration of lymphocytes and upregulated level of Th1 cytokines. The biliary disease often relapses in PBC patients even after liver transplantation. Effective therapeutic strategies for autoimmune liver disease are limited because of its promiscuous pathogenesis. The project will take advantage of a mouse model which will develop spontaneous autoimmune liver disease and progress into liver fibrosis to investigate the mechanism of immune disorder in PBC. Specific aims of this program are stated as follows: 1) To determine the immunological mechanisms of Th1 immune response in liver inflammatory and fibrotic phase of PBC; 2) To investigate the roles of pathogenic liver resident T cells in the PBC mouse model; 3) To evaluate the abnormal phenotype of hematopoietic stem cells in PBC mouse model and explore the relevance between hematopoietic stem cells and immune disorder. Based on our novel PBC mouse model, this project is to investigate the roles of inflammatory cytokines, liver resident T cells, as well as hematopoietic system in autoimmune liver disease. The final aim of this program is to reveal the cellular and molecular mechanisms of immune imbalance in PBC, so as to provide a theoretical basis for elucidating the pathogenesis and for seeking an effective treatment.