原发性胆汁性肝硬化（PBC）是一种器官特异性自身免疫病，发病机制不明且缺乏有效的治疗方法。间充质干细胞（MSCs）具有免疫调节、组织修复等生物学特性，已应用于临床治疗多种自身免疫病。我们前期研究发现PBC患者外周血CD4+CD25+调节性T细胞（Treg）比例下降，且与血清炎症因子IFN-γ等呈显著负相关，异体骨髓MSCs移植治疗polyI:C诱导的PBC动物模型有效，通过免疫调节发挥治疗作用。本课题拟进一步系统研究PBC肝脏局部及全身免疫异常、PBC骨髓MSCs功能异常，并通过观察异体MSCs移植治疗PBC动物模型及患者的疗效，深入探讨治疗机制，为异体MSCs应用于临床治疗PBC患者奠定理论基础。

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease with unknown etiology and lack of effective treatment. Mesenchymal stem cells (MSCs) have immuno-regulatory and tissue repair properties, and have been used for treating many autoimmune diseases. We have demonstrated that peripheral CD4+CD25+ regulatory T cells percentage decreased in PBC patients and was negatively correlated with serum inflammatory factors like IFN-γ. Moreover, allogeneic MSCs transplantation was effective in treating polyI:C induced PBC models, which was mediated by immune-regulation. In the current study, we will determine the local and systemic immune abnormalities in PBC, as well as the functional defect of PBC bone marrow derived MSCs. Here we will illustrate the effect of allogeneic MSCs in treating PBC animal models as well as patients, and further to examine the therapeutic mechanisms. The conclusion of this study may provide deep insight in understanding the effect and mechanism of allogeneic MSCs in treating human PBC.

原发性胆汁性肝硬化（PBC）是一种慢性胆汁性淤积性肝脏疾病，发病率呈增加的趋势。PBC发病机制尚不明确，缺乏有效的治疗方法。本项目研究了PBC患者肝脏局部和全身免疫细胞功能调节异常；应用建立的PBC小鼠模型，分析了其肝脏局部和全身免疫细胞功能；采用间充质干细胞（MSCs）治疗PBC模型并探索了其治疗机制；随访了临床MSCs移植治疗的PBC患者。结果发现PBC患者和模型小鼠肝脏局部和全身存在Th1和Th17细胞过度激活导致的炎症反应，且发现这两种免疫细胞失调与体内Gal-9/Tim-3信号通路异常相关。我们的研究还发现MSCs移植可以改善PBC模型小鼠的肝脏病理、肝功能和自身抗体。深入探讨MSCs治疗PBC小鼠的机制时，发现以下MSCs作用机制：1.通过Gal-9/Tim-3信号通路抑制过度激活的Th1和Th17炎症反应；2.有效修复胆管上皮细胞，抑制其生成丙酮酸脱氢酶复合体E2；3.通过调控caspase通路抑制胆管上皮细胞凋亡；4.抑制胆管上皮细胞自噬活化；这些发现揭示了PBC肝脏局部和全身功能异常的具体免疫细胞及其机制，这些可能成为临床诊断和疗效判断的生物学标记物。另外，阐明了MSCs治疗PBC效果和作用机制，为临床推广应用MSCs治疗PBC患者提供了有力的理论依据。本项目研究成果不仅具有明确PBC与肝脏局部和全身免疫细胞失常关系的科学意义，而且具有MSCs移植常规方法治疗效果不佳的PBC患者的临床意义。