原苏木素A作用于miR-155抑制树突状细胞功能诱导移植免疫耐受的机制研究

Organ transplantation is the sole treatment option for patients facing end-stage organ failure, but allograft rejection is a life-threatening complication. Despite improvements in immunosuppressant treatments over the past few decades, there is still an urgent need for targeted therapies to prevent allograft rejection.The best strategy for transplant rejection is inducing immune tolerance. Dendritic cells (DCs) are professional antigen presenting cells that are critical for initiating immune responses or inducing immune tolerance during organ rejection. Because of its role in regulating DC function and transplantation immunology, microRNA-155（miR-155） is considered a potential target for inducing immune tolerance. Our group first discovered that protosappanin A(PrA) as one effective ingredient from Caesalpinia Sappan L can induce immune tolerance in heart transplanted rat, but the mechanism is unknown. In preliminary studies, we found that PrA inhibited DC function, inducing T cells hypo responsiveness and Treg expansion. PrA inhibited miR-155 levels in DC and transplant recipients, moreover regulation of miR-155 can affect the role of PrA on DC and transplant immunology，and SOCS1 might be one target of miR-155 during this process.These data suggest that PrA might act on miR-155 to modulate DC functional state, thus inducing allograft tolerance. Our study will use cultured DC and rat heart transplantation model, by regulating miR-155 level, to clarify the mechanism of PrA. This study will provide the theoretical basis for PrA clinical application and bring a new hope to overcome transplant rejection.

器官移植排斥是久攻未克的医学难题，而诱导免疫耐受是解决移植排斥的最佳策略。树突状细胞（DC）是诱导免疫耐受的重要靶细胞，microRNA-155（miR-155）由于其对DC功能及移植免疫的关键调控作用，被认为是诱导免疫耐受的潜在靶点。本课题组首次发现中药苏木单体原苏木素A（PrA）能诱导心脏移植免疫耐受，但机制不明。前期研究发现PrA能抑制DC功能诱导Treg，深入探讨分子机制发现PrA抑制DC及移植受体中miR-155水平，调控miR-155表达可影响PrA对DC及移植免疫的作用，提示PrA作用于miR-155，调控DC功能从而诱导移植耐受。基于此，本课题利用体外培养的DC及大鼠心脏移植模型，通过调控miR-155表达，从整体-细胞-分子三个层次，阐明PrA作用于miR-155调控DC功能进而诱导免疫耐受的作用机制。本研究将为PrA的临床应用提供理论依据，也为防治移植排斥提供新策略。

前期研究中我们证实原苏木素A（PrA）能够调控树突状细胞（Dendritic cell，DC）功能并诱导心脏移植免疫耐受，作用机制涉及到Toll样受体4（TLR4）信号通路。miRNA在移植免疫耐受调控中发挥重要作用，我们研究发现PrA能够抑制DC及移植受体中miR-155水平，调控miR-155表达可影响PrA对DC功能的调控作用，下调miR-155表达能够促进PrA的免疫抑制作用，上调miR-155可部分逆转PrA的作用，提示miR-155参与了PrA的作用机制，其中miR-155的下游靶点为SOCS1。同时miRNA芯片筛选及进一步分子生物学验证，我们发现miR-let-7i也参与了PrA诱导心脏移植免疫耐受的作用机制。但PrA如何调控miRNA表达等作用机制尚有待于进一步研究。本研究将为PrA的临床应用提供理论依据，也为防治移植排斥提供新策略。