Xu L H, Fang J P, Huang W G, Xu H G, Weng W J, Kao G S, Le Y
Department of Pediatrics, Second Affiliated Hospital of Zhongshan University, Guangzhou, PR China.
Bone Marrow Transplant. 2007 Oct;40(7):691-8. doi: 10.1038/sj.bmt.1705791. Epub 2007 Jul 30.
Many hematological diseases require long-term transfusion support, which causes production of donor-reactive antibodies in sensitized recipients. Sensitized patients are at an increased risk for graft rejection when they undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we established a highly sensitized murine model to investigate the mechanism of donor graft rejection. After BALB/c mice were repeatedly transfused with allogeneic spleen cells from C57BL/6 mice, there was a significant increase in complement-dependent cytotoxicity in the serum of sensitized mice. For transplantation, 1 x 10(7) bone marrow cells (BMCs) from C57BL/6 mice were injected into lethally irradiated recipient BALB/c mice. Sensitized mice died between 12 and 15 days post-transplantation, while non-sensitized mice remained alive after 28 days. The hematopoietic recovery rate declined over time in sensitized recipients. The homing trace assay showed a rapid disappearance of donor BMCs in the spleen and bone marrow of sensitized recipients. In addition, the recipient cells and antibodies in the sensitized serum were capable of inducing high level of cell- and complement-mediated cytotoxicity to the donor graft. Our finding may explain the impaired hematopoietic stem cell homing and poor hematopoietic engraftment observed in highly sensitized allo-HSCT patients.
许多血液系统疾病需要长期输血支持，这会导致致敏受者产生供体反应性抗体。致敏患者在接受异基因造血干细胞移植（allo-HSCT）时发生移植物排斥反应的风险增加。在此，我们建立了一种高度致敏的小鼠模型来研究供体移植物排斥反应的机制。用C57BL/6小鼠的同种异体脾细胞反复输注BALB/c小鼠后，致敏小鼠血清中补体依赖性细胞毒性显著增加。为进行移植，将1×10(7)个来自C57BL/6小鼠的骨髓细胞（BMC）注入经致死性照射的受体BALB/c小鼠体内。致敏小鼠在移植后12至15天死亡，而非致敏小鼠在28天后仍存活。致敏受者的造血恢复率随时间下降。归巢追踪试验显示，供体BMC在致敏受者的脾脏和骨髓中迅速消失。此外，致敏血清中的受体细胞和抗体能够对供体移植物诱导高水平的细胞介导和补体介导的细胞毒性。我们的发现可能解释了在高度致敏的allo-HSCT患者中观察到的造血干细胞归巢受损和造血植入不良的现象。
