肝星状细胞诱导生成调节T细胞在肝纤维化机制中的研究

项目名称： 肝星状细胞诱导生成调节T细胞在肝纤维化机制中的研究

项目编号： No.31200666

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 免疫学

项目作者： 陈倩

作者单位： 华中科技大学

项目金额： 25万元

中文摘要： 肝纤维化是慢性肝病发展到肝硬化的必经之路，是我国常见疾病和主要死亡病因之一。近年來, 淋巴细胞及细胞因子介导的免疫学机制成为肝纤维化病研究的热点。最新的研究表明，在肝纤维化进程中起核心作用的肝星状细胞（HSC）可直接诱导适应性调节性T细胞（iTreg）的产生，但其在慢性肝病进展中的作用尚不明确。本课题将拟研究iTreg主动参与肝纤维化进程的免疫学机制。将重点阐明肝损伤时，当HSC受血管活性递质一氧化氮激活后诱导产生iTreg，其分泌的TGF-β等炎症因子能反馈活化HSC、诱导淋巴比例失衡，从而加重肝纤维化进程。申请人将利用增强型绿色荧光蛋白(eGFP)－Foxp3转染小鼠模型，动态和准确追踪、并比较在不同病因所致的肝纤维化宿主体内，诱导而生的eGFP阳性iTreg的功能性和差异性。这将为寻找到干预靶点，更有效延缓并阻断肝纤维化提出一套新的细胞免疫学依据。

中文关键词： 肝纤维化；肝星状细胞；适应性调节性T细胞；DNA甲基化；

英文摘要： Objective: to study the role of retinoic acid (RA)-producing hepatic stellate cells (HSC) in liver-associated Treg induction as a result of liver fibrosis. Backgrounds: Liver fibrosis and cirrhosis result from the majority of chronic liver insults and represent a common and difficult clinical challenge of worldwide importance. In China, hepatitis and schistosomiasis are the two most common cause of cirrhosis. At present, the only curative treatment for end stage cirrhosis is transplantation. Recent developments in our understanding confirm that the process is dynamic with respect to the activation of HSCs to differentiate to myofibroblasts for production of extracellular matrix. HSCs within liver lobules are also called vitamin A-storing cells. Under physiological conditions, these cells play pivotal roles in the regulation of vitamin A homoeostasis, liver fibrosis and regulation of hepatic blood flow. Recent studies suggest the RA-producing HSC may be involved in TGF-β-dependent Foxp3+ Treg induction in pathological conditions as the part of the liver tolerance mechanism (1). However, several key issues are not addressed here. First, it is still controversial whether the antigen presenting cell function of HSC is involved in the induction of iTreg. Second, it is unclear whether the liver-associated iTreg induct

英文关键词： Liver fibrosis；HSCs；iTreg；DNA Methylation；