Blimp-1对小鼠allo-HSCT后GVHD发病的调控作用和机制研究

Graft-versus-host disease is the most sever complication of allo-genetic hematopoietic stem cells transplantation (HSCT), which is considered to be induced by donor T cells. Although current means to prevent and treatment of GVHD is clinical effective, GVHD is still the major obstacle in clinical HSCT.So,it is necessary to further explore the molecular mechanisms of GVHD pathogenesis. Blimp-1 is an important regulatory factor to the proliferation and differentiation of T cells, however, the mechanism of Blimp-1 in reguating T cell proliferation and differentiation is not defined. Until now, little is known anbot the role of Blimp-1 in transplantation immunity. In our previous study, we found that disrupt Blimp-1 gene in donor mice T cells could attenuate GVHD, suggesting that Blimp-1 was a novel regulatory factor of GVHD. In this study, we will use donor mice with T cell specific Blimp-1 defeciency and wide type mice to set GVHD models. The regulatory role and effect of Blimp-1 on T cell activation and proliferation in GVHD mice will be explored. Furthermore, the mechanism of Blimp-1 in T cell activation will be studied in transcriptional control and proteomics aspects respectively. If succeed, it will be helpful to further elucidate the mechanism of GVHD pathogenesis, and will provide new strategies for prevention and treatment of GVHD.

移植物抗宿主病（GVHD）是T细胞介导的异基因造血干细胞移植后主要并发症，目前对其防治策略仍有较大局限性，因此很有必要深入探索其发病的分子机制。Blimp-1是T细胞增殖分化的重要调控因子，但对其机制所知有限。目前Blimp-1在移植免疫中的作用罕有报道。我们课题组发现，敲除供鼠T细胞Blimp-1基因可减轻受鼠GVHD，在此基础上，我们提出Blimp-1是GVHD的新调控因子。本研究拟通过常规和T细胞特异性Blimp-1缺陷供鼠建立GVHD模型探索Blimp-1对GVHD的调控作用和对HSCT后T细胞增殖活化的影响；并进一步从转录调控和蛋白组学水平解析Blimp-1调控T细胞活化过程的深层机制。本课题的如期完成有望进一步加深对GVHD发病机理的认识，拓宽GVHD防治的思路。

Blimp-1是T细胞免疫自稳的重要调控者。本课题组前期研究发现敲除供鼠T细胞Blimp-1能够减轻allo-HSCT受鼠GVHD，在此基础上，我们探索了allo-HSCT背景下敲除T细胞Blimp-1对GVHD相关靶器官病理损伤、炎性细胞因子分泌、T细胞增殖及极化等与GVHD发病有密切关系的生物学特性，并探索Blimp-1调控GVHD发病的机制。我们发现敲除供者T细胞Blimp-1显著降低受鼠靶器官GVHD相关的免疫病理损伤，降低血浆炎性因子水平和Th1细胞极化水平，同时，Blimp-1敲除对受者特异抗原诱导的T细胞增殖反应相对较弱。我们发现Blimp-1缺陷效应T细胞CCR7和CCR6上调，而CX3CR1和CXCL6下调。基本阐明Blimp-1通过改变效应T细胞趋化性影响GVHD发病。基于这一思路，我们选择ADAM10这一细胞跨血管迁移所需的分子作为靶点进行后续实验。结果发现敲除供者T细胞ADAM10能极有效的阻断GVHD发病并保留GVL效应。ADAM10是一个活性中心位于细胞膜外的膜定位酶，方便药物作用和进行药物筛选。通过本研究我们初步锁定了一个具有潜力的抗GVHD新靶点，拟进一步进行转化研究。