Stat3敲除的供者T细胞经PD1/PD-L1减轻GVHD保留GVL效应的机制研究

造血干细胞移植（HSCT）是根治白血病的最佳方法之一，但在降低移植物抗宿主病（GVHD），保留移植物抗白血病（GVL）效应减少复发两方面一直很难做到“共赢”。如何有效分离GVHD和GVL是白血病移植治疗领域的难点和热点。Stat3信号通道因其在肿瘤和纤维化中的作用为大家熟知，但在免疫调控方面的功能尚不清楚。申请人在前期Stat3介导免疫耐受的研究中发现，Stat3敲除的供者T细胞能够降低GVHD同时维持GVL效应，其具体机制未明。我们通过预实验和文献复习提出本课题的科学假设：依赖于靶器官高表达PD-L1，Stat3敲除的供者T细胞通过PD1/PD-L1及PD-L1/CD80相互作用减低GVHD同时维持GVL效应。研究将通过体外实验、构建急性GVHD及白血病动物模型，探讨GVHD和GVL分离作用的新机制，为降低白血病移植后复发和减轻GVHD提供理论依据，为临床新方法探索奠定实验依据。

Hematopoietic stem cell transplantation (HSCT) is one of the best methods to cure leukemia, but it has been difficult to achieve "win-win" in alleviating graft versus host disease (GVHD) while preserving graft versus leukemia (GVL) effect and reducing recurrence. It is a difficult and hot spot in leukemia HSCT treatment on how to separate GVHD from GVL. STAT3 signaling pathway is well known for its role in tumor proliferation and fibrosis, but the function in immune regulation remains unclear. In the previous study of Stat3 mediated immune tolerance, the applicant found that the Stat3 knockout donor T cells could reduce GVHD while maintaining GVL effect, but the underlying mechanisms are unclear. We put forward the scientific hypothesis by pre-experiment and literature review, Stat3 knockout donor T cells could reduce GVHD while through preserving GVL is dependent on PD-L1 expression on targeted tissue cells, through PD1/PD-L1 and PD-L1/CD80 interaction. Our study constructs animal models for GVHD and leukemia in vitro to explore new mechanisms in seperating GVHD and GVL, thus providing theoretical basis for reducing relapse and GVHD after HSCT and exploring new clinical methods.