移植物抗宿主病(GVHD)是异基因血干细胞移植(HSCT)和某些大器官移植后致死性并发症，治疗困难，预后凶险。近年来发现固有免疫中主要信号通路TLR/MyD88活化贯穿GVHD发生发展的始终。以TLR/MyD88为靶点探寻防治GVHD的策略已成为国际研究热点。目前的免疫抑制剂(多针对获得性免疫)对治疗以天然免疫占主导的GVHD靶器官(皮肤、肠道、肺)损伤作用有限。经过十年研究，我们成功创制的有完全自主知识产权的MyD88抑制剂不仅具有强大的抗排斥作用，还能调控宿主内效应T和调节性T细胞的平衡，而对移植物抗肿瘤效应(GVT)中起关键作用的T细胞无损害，为HSCT后实现GVHD与GVT的分离提供了理论基础。本项目拟明确药物在抗GVHD中精确的作用机理，探索干预固有免疫和获得性免疫系统的治疗效应，实现GVHD与GVT理想分离，从这些全新抗GVHD策略的探索中找到扫除困扰HSCT主要障碍的新方法。

Until now, graft-versus-host disease (GVHD), with its refractoriness and poor prognosis, is still a lethal complication after allogeneic stem cell transplantation (HSCT) and some other organ transplantations. Recent studies show that the activation of TLR/MyD88 signaling pathway which belongs to the innate immune system follows though the pathogenesis of GVHD. It is a global hotspot for immunologists and pharmacologists to find such an inhibitor of this signaling for decreasing GVHD. Current strategies are based on adaptive immune system and their effects are not so satisfied for the non-solid GVHD target organ, such as skin, gut, and lung, as they are dominated by innate immunity. Based on our continuous efforts on the studies of innate immunity and drug discovery in recent 10 years, we successfully created and synthesized a novel inhibitor, thiazol-amino ramification, TJ-M2010. Our primary results showed that it not only is able to block various TLRs/MyD88 signaling pathways and then show the strong anti-rejection effect, but also can regulate the balance of regulatory T cells and effector T cells in transplantation recipients, other than damage to T cells which are essential to the graft-versus-tumor (GVT) effect. It provides a theoretical basis for the separation of GVHD and GVT after HSCT. In this proposal, further studies will focus on the TJ-M2010 action of anti-GVHD, and three novel strategies, including modulation of innate immune to avoid GVHD, synergism to combine with anti-adaptive immune, and separation of harmful GVHD and beneficial GVT effect after HSCT will be explored and aim at providing potential new opportunities to remove the biggest obstacle of HSCT.