肝脏树突状细胞在移植肝区域免疫中的作用及机制研究

The liver is considered as a unique lymphoid organ, exhibiting a distinctive form of immune privilege. However, the mechanisms of local regulation of immune responses in the liver remain unknown. Accumulating evidence has showed that hepatic non-parenchymal cells play an important role in regulating regional immune response of liver. Our preliminary findings suggested that liver dendritic cells (LDC) determine the fate of liver allografts towards immune rejection or tolerance. The present research is designed to analyse the characteristic of LDC, observe the origin , migration and distribution of LDC, and investigate the sophisticated mechanisms of liver dendritic cells in the regional immune response in the liver, on the basis of clinical data of liver transplantation and mouse model of liver transplantation. Immunosuppressive cytokines (such as IL-10, TGF-β, Galectin-1, IL-27), inhibitory signals (B7-H1/PD-1, TIM-3/Galectin-9), the distinctive liver extracellular matrix and the cell network will be focused on to study. As the underlying molecular mechanisms have only recently begun to emerge, our research is timely and might shed new light on the knowledge of liver regional immune system. We further provide the new evidences for improving the immunology theory of liver, explore the potential of liver dendritic cells to induce long-term stable liver transplant tolerance, and find new targets for immune therapy.

肝脏是机体重要的免疫器官, 但迄今为止国内外对于肝脏区域免疫基本属性及其调控机制知之甚少。目前已知，肝脏非实质细胞是调控肝脏区域免疫的主导细胞群。我们前期研究发现，肝脏树突状细胞（LDC）对于决定移植肝发生免疫排斥或耐受起关键作用。 本项目拟以临床肝移植和小鼠肝移植为研究平台，以LDC为研究对象，分析LDC的基本属性，观察LDC的起源、动态迁徙和定植过程，探讨LDC在移植肝区域免疫特性中的作用及机制，深入研究肝脏局部的细胞因子网络（IL-10、TGF-β、Galectin-1、IL-27等）、抑制性信号通路（B7-H1/PD-1、TIM-3/Galectin-9等）以及肝脏独特的细胞外基质所构成的免疫微环境和细胞相互作用网络在LDC调控肝脏区域免疫的作用及机制，以期为丰富和完善肝脏区域免疫学理论提供新的科学证据，探索诱导长期稳定肝移植免疫耐受的方法和策略，并寻找新的免疫治疗靶点。

本项目以临床肝移植和小鼠肝移植为研究平台，以肝脏树突状细胞（DC）等免疫细胞为研究对象，探讨其在肝脏区域免疫特性中的作用及机制，以期为丰富和完善肝脏区域免疫学理论提供新的科学证据，并探索诱导长期稳定的供者特异的肝移植免疫耐受的方法和策略。项目阐释了肝脏耐受性树突状细胞、间充质干细胞在肝脏移植过程中诱导肝移植免疫耐受与减轻肝脏缺血再灌注损伤的机理，并创新性发现供肝T/B细胞在移植物抗肿瘤效应中的重要作用。首次确定肝癌缺氧微环境诱导巨噬细胞是促进肝癌抗PD-1/PD-L1抵抗现象的始动因素，并建立肝癌抗PD-1/PD-L1免疫治疗新策略。揭示了HJV基因在肝脏区域免疫调控中的关键调控作用。解析了肠道微生态和肝脏区域免疫的相关性，描述了肠道微生态分群、表型和免疫学因素；制定了肝移植术后免疫抑制剂撤除路线图，阐明了CD8+CD28-T细胞、CD16+单核细胞、CD19+IL10+ B细胞等一系列关键免疫细胞在肝移植术后排斥反应及免疫耐受中的作用。本项目培养了一批具有国际影响力、临床与基础紧密结合、多学科专业交叉配合与优势互补的高水平科技人才。