TIM-1+ 调节性B细胞在小肠移植中调控排斥反应并诱导免疫耐受的作用及其机制的研究

B cells are best known for their production of antibodies and their protection against infection. However, the ability of B cells to negatively regulate cellular immune responses and inflammation has been reported recently. A small group of B cells that possess regulatory functions were named "regulatory B cells" (Bregs), but the phenotypes of Bregs remain uncharacterized. Recent studies show that "TIM-1+ B cells" can be a better phenotype for Bregs. There are strong evidences that Bregs play important roles in regulating autoimmunity, cancer and infectious diseases, however, little is known concerning its role and mechanism in allograft rejection. Their role in inducing allograft tolerance has attracted great interest recently. Our previous studies have shown that Bregs can be identified by expression of TIM-1. TIM-1+ Bregs can inhibit proliferation of T cells in mixture lymphocytes reaction in vitro, TIM-1+ Bregs can also inhibit allograft rejection in small bowel transplantation models in vivo and the role of regulation is antigen specific. In this project, after establishing allogeneic small bowel transplantation in mice, we plan to use CD22 mAb to deplete most Bregs in recipients or transfer different number of TIM-1+ Bregs to recipients. In order to study the role and mechanism of Bregs in regulating allograft rejection and inducing tolerance on post-operative day 7 (POD7), we are going to compare several indexes in different groups, including graft pathological morphology changes, various types of immune cells and their immune factors. Clarifying the role and mechanism of Bregs in allograft transplantation would be a solution for induction of donor-specific tolerance, and will provide a new choice for studying long-term graft function as well as to improve the quality of patient's life.

调节性B细胞（Bregs）为一群具有特异性免疫调节功能的细胞亚群。最新研究表明，TIM-1+B细胞可能成为其更好表型。多项研究已证明Bregs在自身免疫性疾病、恶性肿瘤及炎症性疾病中发挥着重要的免疫调节作用，但对其在移植免疫中的作用尚不明确。如何通过Bregs诱导免疫耐受成为目前移植免疫学研究热点。我们的研究已证实TIM-1+B细胞为Bregs更好表型，并建立了分离获取TIM-1+Bregs的方法，通过体外混合淋巴细胞培养及体内TIM-1+Bregs输注初步证实TIM-1+Bregs能够特异性地抑制移植物排斥反应。本项目拟在建立小鼠小肠移植模型的基础上，通过清除受体大部分Bregs和对受体输注不同数量TIM-1+Bregs两种途径，比较各组移植物病理学与受体各型免疫细胞及相关因子的变化，研究Bregs在小肠移植中调控排斥反应并诱导免疫耐受的作用及其机制，为诱导移植免疫耐受提供一种新的策略。

调节性 B 细胞（Bregs）为一群具有特异性免疫调节功能的细胞亚群。研究表明，TIM-1+ B 细胞目前为调节性 B 细胞特异性表型。多项研究已证实 Bregs 在自身免疫性疾病、恶性肿瘤及炎症性疾病中发挥着重要的免疫调节作用，但对其在移植免疫中的作用尚不明确。如何通过 Bregs 诱导免疫耐受成为目前移植免疫学研究热点。 我们的研究再次证实 TIM-1+B 细胞为 Bregs 更好表型，并建立了分离获取 TIM-1+ Bregs 的方法。我们在国内率先建立了小鼠小肠移植模型，同时在建立了小鼠小肠移植模型的基础上，通过对受体小鼠输注CD22 mAb 去除体内大部分Bregs以及对受体输注TIM-1+ Bregs，比较各组受体移植物病理学与受体各型免疫细胞（T细胞、B细胞、DC细胞及Th1/Th2/Th17/Tregs）及相关因子（IL-2/ IL-4/ IL-10 /IL-17/IFN-γ/TGF-β）的变化，证实了TIM-1+ Bregs 能够特异性地减轻移植物的排斥反应，Bregs 在小肠移植中可能通过平衡Th1/Th2/Th17细胞比例、上调调节性T细胞表达，特异性调控排斥反应并诱导移植物免疫耐受，为诱导移植免疫耐受提供了一种新的策略。项目负责人作为第一作者和通讯作者已发表基金标注SCI收录论文1篇，以及1篇国际会议论文，主要研究成果有1篇论文已成稿待发表。项目在研究成果与人才培养方面已基本达到预期目标，项目经费按预算合理使用。