全反式维甲酸诱生的tisTregST2细胞调控异基因造血干细胞移植后GVHD与GVL的作用和机制

如何有效分离移植物抗宿主病（GVHD）与移植物抗白血病（GVL）效应是异基因造血干细胞移植亟需解决的问题。Treg细胞回输治疗可防治GVHD而不损伤GVL效应。我们的早期研究发现，tisTregST2细胞（组织特异性Treg）较Treg细胞具更强的组织修复及免疫调节功能，减轻GVHD严重度。因此，开发能够增强tisTregST2细胞生成及功能的方法将具有极大的临床价值。我们的预实验发现，全反式维甲酸（ATRA）可体外促进Treg细胞表达tisTregST2表型分子、迁移受体CXCR3及组织修复蛋白，过继转输ATRA-Treg细胞可减弱小鼠GVHD。本课题中，我们将以同种/异种移植GVHD白血病鼠为模型，探讨ATRA促进tisTregST2细胞生成、增强其向GVHD靶器官迁移及组织修复的作用，阐明ATRA-Treg细胞分离GVHD与GVL效应的作用及机制，为Treg细胞回输治疗提供新的策略。

Preventing graft-versus host disease (GVHD) while preserving graft-versus leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (HCT) is essential for patients. Adoptive transfer of regulatory T cell (Tregs) after HCT was demonstrated to separate GVHD and GVL effectively. We have recently reported that tisTregST2 cells showed increased abilities in tissue recovery, immuno-suppression effect and ameliorating GVHD than normal Tregs. Thus investigating strategies to enhance tisTregST2 cells generation will provide new insight in cellular therapy for preventing GVHD. Our preliminary data revealed that all-trans retinoic acid (ATRA) treated Tregs upregulated the expression of ST2, KLRG1, BATF, CXCR3 and AREG in vitro. Adoptive transfer of ATRA-Tregs ameliorated murine GVHD. Here we hypothesize that ATRA promotes tisTregST2 cells generation via BATF pathway. ATRA generated tisTregST2 cells could separate GVHD and GVL via promoting tisTregsST2 cells migration into GVHD target organs and its tissue recovery capability. Both acute GVHD and xenograft GVHD leukemia murine models will be used to demonstrate the hypothesis. The idea that adoptive transfer of ATRA generated tisTregST2 cells will provide a novel and efficient cellular therapeutic avenue to prevent GVHD while to maintain GVL effect.