FasL基因修饰树突状细胞的抗白血病作用及其机制

Graft versus leukemia effect of FasL-modified dendritic cells and its mechanism

目的:选择性去除骨髓移植物中异基因反应性淋巴细胞,特异性抑制移植物抗宿主病(graft versus host disease,GVHD)并保留移植物的抗白血病(graft versus leukemia,GVL)作用。方法:分别把未经处理的、溶T淋巴细胞处理的和以FasL基因修饰树突状细胞(FasL-DC)处理的3组小鼠骨髓细胞移植物移植给已经接种P815肿瘤细胞的BALB/c受体小鼠,然后观察比较各组小鼠存活情况,并用51Cr释放法检测移植后2个月受体小鼠T淋巴细胞的CTL活性。结果:致死剂量(9Gy)照射的白血病受体鼠在接受经FasL-DC处理的供体骨髓细胞移植后,生存期显著延长,2个月时生存率为40%,对照组在1个月内全部死亡。51Cr释放法检测证实,FasL-DC处理组的T淋巴细胞对P815细胞保持较强的杀伤活性。结论:转染FasL基因的DC可有效去除骨髓移植物中异基因反应性T淋巴细胞,移植用该方法处理过的骨髓,不但能够有效抑制GVHD的发生,同时也可以保留移植物的抗肿瘤作用。

Objective： To specifically inhibit the graft versus host disease （GYHD） and keep graft versus leukemia （GVL） effect of bone graft through selective deletion of alloreactive lymphocytes from haematopoietic stem cell grafts, Methods： BALB/c mice dendritic cells genetically engineered to express FasL were cultured with C57 BL/6 mice stem cell grafts, and the pretreated stem cell grafts were used in a C57BL/6 to BALB/c mice GVHD/leukaemia model system （H- 2^b→H-2^d ）. Untreated stem cells and those with T lymphocytes deleted were taken as controls. Then the survival of mice was observed and compared, ^51Cr release test was used to determine CTL activity of recipient mice 2 month after transplantation. Results： Mice receiving donor haematopoietic stem cell grafts pretreated with FasL-DC did not develop GVHD after lethal dose irradiation （9 Gy） and their survival period was greatly prolonged, with the survival rate being 40% after 2 months ; mice in the control groups all died in 30 day. Result of ^51 Cr release test showed that in FasL-DC group T cell had strong cytoxicity on P815 cells. Conelusion：DC transfected with FasL gene can effectively remove alloreactive T lymphocytes in bone marrow graft. The bone marrow treated with this kind of technique can not only inhibit GVHD but also keep the GVL effect of haematopoietic stem cell grafts.