独创的MyD88抑制剂靶向防治GVHD的新策略及机理

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.

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。

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。我们的实验结果表明GVHD小鼠靶器官组织中TLR4/MyD88/NF-κB信号通路呈明显的活化状态，基因转录和蛋白翻译均有增强，且与GVHD病情呈显著的正相关，TJ-M2010-5可抑制 LPS导致的DC成熟与活化，抑制DC细胞内MyD88信号通路的传递，抑制其分泌IL-1α、 IL-10、IL-12、IL-18等炎性因子；TJ-M2010-5通过抑制 DC成熟而阻断混培体系中的异基因淋巴细胞增殖；TJ-M2010-5通过改善GVHD小鼠体内炎性环境，减轻靶器官病理损伤与细胞坏死凋亡，促进组织修复，促进嵌合体形成，明显延缓 GVHD 进展；TJ-5 治疗荷瘤GVHD小鼠过程中对移植物GVT效果并无明显的抑制作用。基于新型 MyD88 抑制剂，联合 CD40/CD40L 阻断，行双系统联合抑制，能显著改善，甚至逆转 GVHD 进展；TJ-M2010-5 治疗 GVHD 的同时不影响 GVT 作用，TJ-M2010-5 通过对肿瘤细胞的直接杀伤和其干预后 GVT 效应的保留来减少骨髓瘤的复发，延长荷瘤小鼠的生存期。TJ-M2010-5 可通过诱导受体 Treg 的生成而发挥一定的 GVT 效果。这为临床上治疗GVHD以及GVHD与GVT分离提供新的策略。