T细胞在单倍型相合移植较HLA相合同胞移植具有更强抗白血病作用中的机制及转化研究

针对临床新问题“HLA相合同胞移植（MSDT）总是首选移植方式吗？”，申请人发现：①单倍型相合移植（Haplo-SCT）较MSDT有更强抗白血病（GVL）作用；②移植后单倍型相合T细胞（Haplo-T），尤其CD8+T细胞，功能强于HLA（人）/MHC（鼠）相合同胞T细胞（Match-T）；③PRDM1与T细胞功能密切相关。本项目拟以T细胞为核心、以PRMD1对T细胞调控为切入点，利用临床和小鼠模型（一个核心、一个切入点、两个模型），借助多组学等技术研究移植后Haplo-T和Match-T细胞的功能差异、绘制其转录组和基因组图谱，明确Haplo-T和Match-T细胞PRDM1等的表达差异，从PRDM1调控T细胞功能的角度阐明“Haplo-SCT较MSDT有更强GVL作用的免疫学机制（科学问题）”；成果转化：①改写“首选MSDT”的供者选择原则；②确定具备GVL效应、可临床应用的人T亚群。

Currently, human leukocyte antigen-matched sibling donor transplantation (MSDT) remains the preferred modality. Previous studies by applicant showed that i) treating pre-transplantation minimal residual disease positive acute leukemia patients with haploidentical SCT could achieve stronger graft-versus-leukemia (GVL) effects than that of MSDT. ii) haploidentical T cells, especially CD8+ T cells, are functionally stronger than HLA/MHC-matched sibling donor T cells. iii) PRDM1 is associated with T cell function. Therefore, the aim of this project is to elucidate mechanisms of stronger GVL effects after haploidentical SCT than that of MSDT in the view of T cells based on the clinical cohort and the mice model. The phenotypical and functional differences, especially genome map and transcription map, between haploidentical T cells and HLA/MHC-matched sibling donor T cells were investigated using cellular and molecular techniques as well as RNAseq and ATACseq. These data may lead to the elucidation of differences in gene and transcription factors, such as PRDM1, between haploidentical T cells and HLA/MHC-matched sibling donor T cells. This project will not only elucidate the mechanism underlying the clinical question that haploidentical SCT had a stronger GVL effect than that of MSDT, but also contribute to establish a novel criterion for donor selection that is haploidentical SCT might be chosen first for some subgroup patients, for example cases with pre-transplantation minimal residual disease. The results of this project may also contribute to the establishment of adoptive transfer of T cell subsets for enhancing the GVL effect.