供者来源调节性B细胞对移植物抗白血病效应的调控作用及其机制

The separation of graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD) remains a challenge for patients who underwent allogeneic stem cell transplantation. Studies by the applicant suggested that naïve T cells, not memory T cells, were associated with acute and chronic GVHD. He also found that donor derived regulatory B cell (Breg) could decrease the incidence of acute GVHD via regulating Th1, Th17 and regulatory T cells. Therefore, the applicant supposed that donor derived Breg could retain GVL effects, simultaneously decrease the incidence of acute GVHD. Therefore, the aim of this project is to explore the roles of donor-derived Breg on GVL effects and the mechanisms of which through regulating naïve T cells and memory T cells as well as perforin and Fas ligand. The elucidation of the effects and mechanisms of donor-derived Breg in GVL effects after allogeneic stem cell transplantation may not only add new knowledge to transplant immunology, but also pave a road for the establishment of a novel method, adoptive transfer of donor-derived Breg, for the separation of GVL effects and GVHD in allogeneic stem cell transplant settings.

移植物抗白血病(GVL)效应和移植物抗宿主病(GVHD)分离是造血干细胞移植领域亟待解决的问题。申请人的工作提示初始T细胞是急、慢性GVHD的主要效应细胞，记忆T细胞与GVHD无关；供者来源的调节性B细胞(Breg)可通过调控Th1/Th17/调节性T细胞降低急性GVHD发生率。由此提出如下科学假说(问题)：供者来源Breg能在有效保留GVL效应的同时降低GVHD发生率。本课题拟以Breg为主线、以Breg对初始和效应T细胞的调节作用为切入点、以穿孔素和FasL为靶分子，利用小鼠白血病移植模型和HSCT临床模型，阐明供者来源Breg对GVL效应的调控作用，探讨Breg对初始和效应T细胞不同调节作用，揭示其细胞学机制，从穿孔素和FasL角度阐明其分子机制。意义在于阐明供者来源Breg对GVL效应的调控及其细胞/分子机制，为建立GVL效应和GVHD分离新方法——过继性输注Breg，奠定基础。

借助动物模型，课题组证实了粒细胞集落刺激因子（G-CSF）动员的供者来源的调节性B细胞（Breg）在降低急性移植物抗宿主病（GVHD）的同时，有效保留了T细胞介导的移植物抗白血病（GVL）效应。临床队列研究证实，采集物中高剂量Breg（≥1.63×107/kg）的患者II–IV度急性GVHD累积发生率显著低于低剂量Breg组（＜1.63×107/kg）。高剂量Breg组和低剂量Breg组患者的累积复发率（CIR）、非复发死亡（NRM）、无病生存（LFS）和总体生存（OS）差别无统计学意义。上述结果为建立GVL效应和GVHD分离的新方法——过继性输注Breg，奠定了基础。课题组还借助回顾性和前瞻性临床队列，发现对于移植前微小残留病（MRD）阳性的ALL患者而言，与接受MSDT的患者相比，接受单倍型相合移植（Haplo-SCT）的患者具有更低的CIR、更高的LFS和OS，该结果提示Haplo-SCT的GVL效应优于MSDT，通过供者选择可以部分达到分离GVHD与GVL的目标。此外，课题组还证实了MRD可以预测接受Haplo-SCT的ALL患者移植预后，且移植前后MRD动态变化较单一时间点能更好地预测移植预后。目前，课题组在J Hematol Oncol、Oncoimmunology等学术期刊发表SCI论文5篇，培养毕业博士生1名，硕士生2名。