SR-BI对DC分化成熟及同种免疫刺激活性的调节作用及机制研究

Dendritic cells (DCs) play an important role in initiating and maintaining tolerance, manipulation of DC by control of their maturation and differentiation, or genetic engineering of DC to express immunosuppressive molecules, offers potential for therapy of allograft rejection and autoimmune disease. Scavenger receptor BI (SR-BI) is a high-density lipoprotein (HDL) receptor. In addition to regulating HDL metabolism, recent studies indicated that scavenger receptor class B type I (SR-BI) participate in immune regulation..Our previous studies demonstrated that SR-BI-null mice exhibited impaired lymphocyte homeostasis and autoimmune disorders as shown by splenomegaly and.imbalanced expansion of T and B lymphocytes in the spleens. Importantly, the activated T, B lymphocytes and DC were increased, the percentage and the.number of effector memory CD4+T were significant increased. SR-BI-null mice developed systemic autoimmune disorders characterized by the.presence of autoantibodies in circulation, the deposition of immune complexes in kidney. These results reveal that SR-BI plays a crucial role in maintaining immune tolerance and lymphocyte homeostasis. However, the underlying mechanisms on regulation of DC are not well defined. In this study we will investigate the effects of adenovirus vector-mediated upregulation of SR-BI or blocking SR-BI with monoclonal antibody on DC differentiation and function for CD4+ T Cells mediated allograft rejection. The involved signaling pathways TLR4/NF-KB will be also investigated. This study is helpful for further elucidating the mechanisms of SR-BI immune regulation and developing more effective strategy for immune tolerance.

树突状细胞（DC）作为诱导和维持机体免疫耐受的重要靶点在移植和自身免疫性疾病领域受到人们关注。B族I型清道夫受体(SR-BI) 是目前唯一确认的HDL受体，最近研究发现除调节脂代谢外，SR-BI还参与免疫调节和信号通路调节等多个方面。我们前期研究发现SR-BI基因缺失导致小鼠淋巴细胞稳态受损和自身免疫性疾病，这提示SR-BI在维持机体自身免疫耐受和活化外周T、B细胞中发挥重要作用，但其作用机制是否与调控DC相关尚不清。我们拟利用SR-BI重组表达载体及抗体干预DC中SR-BI水平，明确其对DC分化成熟及功能的影响，并以TLR4/NF-KB通路为切入点探讨其分子机制；进一步应用体外细胞培养及体内皮肤移植模型，研究干预SR-BI受体对DC刺激的同种CD4+T细胞免疫应答及同种皮肤移植免疫排斥反应的影响，以期达到深入阐明SR-BI免疫调控机理，并寻求更为有效免疫耐受策略的目的。

树突状细胞(DC)，是目前已知的功能最强的抗原递呈细胞，参与抗原识别，加工处理和提呈，DC作为诱导和维持免疫耐受的重要靶点在移植和自身免疫性疾病领域受到人们关注。研究发现，DC表面清道夫受体(scavenger receptor, SR)参与DC细胞病原体清除、动脉粥样硬化形成、凋亡细胞识别等多个方面。本课题研究了SR-BI对DC分化成熟及同种免疫刺激活性的调节作用及机制，研究发现SR-BI明显抑制LPS诱导的骨髓来源DC成熟相关表型（CD80、CD86、MHCII类分子）的表达、影响DC分泌IL-10、IL-12水平、降低DC促CD4+T细胞增殖及分泌Th1型细胞因子的能力，SR-BI干预的DC能够明显延长同种皮肤移植皮片的存活时间，为探索通过SR-BI干预的DC预防同种免疫排斥反应提供依据。此外，由于近期SR-BI在肿瘤的发生发展中的作用逐渐受到人们关注，研究组在完成原有课题计划的基础上，也增加的相关研究，并初步证实SR-BI在肺癌组织表达增高并能增加肺腺癌A549细胞侵袭及增殖能力。