供者来源的调节性B细胞在急性GVHD发病中的负调控作用及其机制

Acute graft-versus-host disease (GVHD) remains one of the lethal complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Currently, the immunological mechanisms of acute GVHD have not been completely elucidated. Therefore, researchers both at home and abroad paid more attention to the role of effectvie immune cells and regulatory immune cells played in the pathogenesis of acute GVHD. Regulatory B cells (Breg) is a new kind of immune cells and has regulatory effects on T cells and regulatory T cells (Treg). Our studies suggested that donor-derived Breg may negatively regulate acute GVHD and decrease the incidence of acute GVHD after allo-HSCT. We also demonstrated that donor-derived Th17 and Th1 cells are main effective cells of acute GVHD. The donor-derived Treg can prevent the onset of acute GVHD following allo-HSCT. Therefore,the aim of this project is to investigate the effect of Breg in acute GVHD and the mechanisms of which through regulating Th17,Th1,and Treg using mouse transplant model and clincial transplant protocol. The eluciation of the effects and mechanisms of Breg in acute GVHD may not only add new notion to the immunological mechnisms of acute GVHD, but also contribute to establish a novel method,adoptive transfer of Breg,for prophylaxis and/or therapy of acute GVHD.

急性GVHD是异基因造血干细胞移植后的主要合并症和死亡原因之一，其发病的免疫学机制仍不十分清楚。调节性B细胞(Breg)是新近发现的一种新型免疫调节细胞，可对效应性T细胞和调节性T细胞(Treg)进行免疫调节。申请人的前期工作提示供者来源的Breg可能负调控急性GVHD、降低其发生率。申请人还发现供者来源的Th17和Th1是急性GVHD的主要效应细胞，供者来源的Treg可降低移植后急性GVHD的发生率。本课题拟以Breg为核心、以Breg对Th17/Th1/Treg的调节为主线、利用小鼠和临床移植模型(一个核心、一条主线、两种模型)，阐明供者来源的Breg通过调节Th17/Th1/Treg这一细胞学机制在急性GVHD发病中起负调控作用(科学问题)。本课题的意义：①阐明供者来源Breg负调控急性GVHD的作用及机制；②为临床上建立过继性输注供者来源Breg防治急性GVHD的新方法奠定基础。

课题组借助发现粒细胞集落刺激因子（G-CSF）动员的供者来源Breg通过体内扩增Treg，调控Th1/Th2/Th17分化降低急性移植后GVHD发生率，但不影响抗白血病作用。团队借助CD4/CD8比值将Allo-SCT患者分为急性GVHD发生的高、低危人群，将高危人群随机分为糖皮质激素预防组和对照组；结果显示激素预防不仅将II-IV度急性GVHD发生率降低27%，而且显著降低100天内激素用量、继发性高血压和股骨头坏死的发生率。课题组长期随访证实小剂量激素预防显著降低了中、重度慢性GVHD的发生率，改善了无GVHD无复发生存。课题组还发现单倍型相合移植后30天初始Treg快速重建可降低移植后II-IV度急性GVHD发生率，非遗传母系抗原不合可以促进移植后初始Treg重建，从人体角度提示Treg是NIMA诱导免疫耐受的机制之一。课题组还发现年轻供者的采集骨髓和外周血混合移植中CD3+T细胞、CD3+CD8+T细胞、单核细胞以及CD3+CD4-CD8-T细胞的数量高于年老供者，提示移植时应该选择年轻供者。目前在J Clin Oncol、Oncoimmuology、Biol Blood Marrow Transplant等学术期刊发表SCI论文5篇，培养毕业博士生2名，在读硕士生1名。