髓源抑制性细胞在胆道闭锁中的数量与功能改变及其对免疫调节的影响

Enhanced T cell mediated bile duct immuoreaction and reduced regulatory T cell may contribute to the hyper immune responses in biliary atresia (BA), but the cause of it is unclear. Myeloid-derived suppressive cell (MDSC) is highly expressed in neonatal infant and it is important to control the T cell activation and the promote regulatory T cell proliferation. The function of the MDSC in biliary atresia is not detail studied previously. Our preliminary data showed reduction of MDSC in biliary atresia patients was present at biliary atresia. MDSC related cytokine interleukin-6 expression in liver tissue was reduced. Furthermore, the Stat3 signaling pathway which control MDSC function was down-regulated in the patient's samples. For detail understand if downregulated Stat3 in BA can through the alternation of MDSC both in number and function to cause the dysregulation of immune response, in this project, we will further enlarge the clinical sample size and to use mouse rhesus rotavirus induced biliary atresia model (both inflammatory type and fibrosis type), in addition to use co-culture study of interaction betwen isolated MDSC with immune cells and fibroblast, to further analyze the number and function of MDSC in different stages of biliary atresia. Finally, by using specific antibodies and drugs to inhibit or deplete the MDSC or though adoptive transfer MDSC in BA model to analyze the effect of MDSC in the progress of biliary atresia in animal models. The success of this study will further increase our understanding of cellular immunology of biliary atresia and provide an insight to the future clinical management

T细胞介导的过强胆道免疫反应及调节性T细胞下降构成的免疫失调是胆道闭锁（biliary atresia，BA）形成的关键因素，但成因未知。新生儿期髓源抑制性细胞(MDSC)存在高表达，对T细胞的功能及调节性T细胞形成有重要影响。预实验结果显示BA患者MDSC的数量显著下降，与其功能调控相关的细胞因子白介素6及细胞内信号通路gp130/Stat3的表达降低。为研究BA病理状态下低表达的Stat3可否通过改变MDSC数量与功能改变导致BA免疫失调，本课题在扩展临床病基础上辅以小鼠炎症及纤维化BA模型，运用体外分离MDSC与其它免疫细胞及纤维母细胞共培养，重点研究MDSC数量及功能与BA炎症及纤维化的相关性并探讨其机制；并通过改变动物外周血及肝内MDSC数量及功能，进一步观察对BA进程的影响。本课题的完成，对全面了解BA细胞免疫的机制有重要意义，为临床药物治疗BA提供了新思维。

T细胞介导的过强胆道免疫反应及调节性T细胞下降构成的免疫失调是胆道闭锁（biliary atresia，BA）形成的关键因素，但成因未知。新生儿期髓源抑制性细胞(MDSC)存在高表达，对T细胞的功能及调节性T细胞形成有重要影响。预实验结果显示BA患者MDSC的数量显著下降，与其功能调控相关的细胞因子白介素6及细胞内信号通路gp130/Stat3的表达降低。为研究BA病理状态下低表达的Stat3可否通过改变MDSC数量与功能改变导致BA免疫失调，本课题在扩展临床病基础上辅以小鼠炎症及纤维化BA模型，运用体外分离MDSC与其它免疫细胞及纤维母细胞共培养，重点研究MDSC数量及功能与BA炎症及纤维化的相关性并探讨其机制；并通过改变动物外周血及肝内MDSC数量及功能，进一步观察对BA进程的影响。本课题的完成，对全面了解BA细胞免疫的机制有重要意义，为临床药物治疗BA提供了新思维。