HLA-DPB1和DPA1等位基因错配引发HSCT后异体高反应性免疫应答的机制研究

研究表明供受者HLA相合或错配与HSCT预后相关，但其机制尚不清楚。申报者前期研究发现:非血缘和亲缘供者与受者HLA-10/10全相合，却约有69-97%存在HLA-DPB1, DPA1等位基因错配，且其可允许和不允许错配类型影响HSCT的OS。据此推测:当供受者DP位点全相合时，APC可捕获肿瘤细胞，由DP分子限制性递呈给活化的CD4+CTL细胞直接杀伤白血病细胞；当错配时外源性抗原由DP分子递呈，受者CD4+Th1细胞识别移植抗原，被激活和释放多种炎性因子而产生GVHD。本项目将从DP位点可允许和不允许错配模式的角度，采用NGS、定量PCR、流式等技术，建立中国人群DPB1、DPA1的CWD数据库、TCE模型、FD阈值、可允许和不允许错配分析软件、体外杀伤模型，并结合临床病例，阐明DPB1、DPA1基因错配及高表达引发HSCT后GVHD和复发的不同免疫应答机制并精准指导供者的选择。

Recent clinical study confirmed that HLA match or mismatch between recipients and donors is associated with HSCT prognosis, but the mechanism is unclear. Our study found that about 69-97% of HLA-A, B, C, DRB1 and DQB1(10/10) matched recipient-donor existed mismatches of HLA-DPB1 and DPA1 allele, and the permissive and nonpermissive mismatches were important factors that affected the occurrence of GVHD and recurrence after HSCT. It was speculated that when HLA-DP matched or TCE was within the same group between recipient-donor, APCs could capture tumor cells and then restrictively presented to activated CD4+ CTL cells by DP molecular to directly kill leukemia cells. On the contrary, when DP mismatched, recipient’s CD4+ Th1 cells recognized exogenous antigen presented by the DP molecule, was activated and released a variety of inflammatory factors, thus resulting in severe GVHD. From the point view of permissive and nonpermissive mismatch model of DPB1 and DPA1 allele, this project will establish a Chinese population DPB1, DPA1 CWD database, TCE model, FD threshold score, permissive and nonpermissive pattern, experimental model of T cell killing function, combined with clinical cases, to explore the mechanism of occurrence and development of allogeneic hyperreactive immune response caused by DPB1 and DPA1 mismatch after HSCT, and further clarify that DPB1 and DPA1 alleles are independent targets for predicting the prognosis of HSCT. These findings provide important theoretical basis and new strategies for the clinical prevention and treatment of GVHD and leukemia recurrence in HSCT.