Hematology, Graduate School of Medicine, Osaka Metropolitan University, Abeno, Osaka, Japan.
Hematology, Graduate School of Medicine, Osaka Metropolitan University, Abeno, Osaka, Japan.
Exp Hematol. 2023 Jul;123:56-65. doi: 10.1016/j.exphem.2023.04.003. Epub 2023 Apr 23.
Posttransplant cyclophosphamide (PTCy) is an effective prophylaxis for graft-versus-host disease (GVHD) due to its suppression of donor-derived alloreactive T cells in allogeneic hematopoietic stem cell transplantation (HSCT). The graft-versus-leukemia (GVL) effect is an antileukemia effect induced by donor-derived alloreactive T cells, similar to GVHD, whereas no studies have demonstrated the association between the dynamics of donor-derived alloreactive T cells and impairment of the GVL effect after HSCT with PTCy. We herein evaluated the dynamics of donor-derived T cells expressing a functional marker for alloreactivity, programmed cell death-1 (PD-1), in a murine HSCT model with PTCy. We showed that PTCy was associated with the development of leukemia cells and the decreased survival probability in an HSCT model with leukemia cells, whereas PTCy could ameliorate GVHD and increased the survival probability in the HSCT model without leukemia cells. We revealed that the percentages of PD-1 expressing donor-derived CD8/CD4 alloreactive T cells, with the exception of CD44 memory T cells, in the recipient spleen were suppressed with PTCy, and that donor T-cell chimerism levels were decreased early after HSCT with PTCy. Our results suggest that PTCy correlated with the impairment of the GVL effect and the amelioration of GVHD through the suppression of PD-1 expressing donor-derived CD8/CD4 alloreactive T cells after HSCT.
移植后环磷酰胺（PTCy）通过抑制异基因造血干细胞移植（HSCT）中供体来源的同种反应性 T 细胞，是预防移植物抗宿主病（GVHD）的有效方法。移植物抗白血病（GVL）效应是供体来源的同种反应性 T 细胞诱导的抗白血病效应，类似于 GVHD，但是，尚无研究表明 PTCy 后 HSCT 中供体来源的同种反应性 T 细胞的动态变化与 GVL 效应的损害之间存在关联。我们在 PTCy 的小鼠 HSCT 模型中评估了表达同种反应性功能标志物程序性细胞死亡蛋白 1（PD-1）的供体源性 T 细胞的动态变化。我们表明，PTCy 与白血病细胞 HSCT 模型中白血病细胞的发展和生存概率降低有关，而 PTCy 可以改善 GVHD 并增加无白血病细胞 HSCT 模型中的生存概率。我们揭示了 PTCy 可抑制受体脾脏中表达 PD-1 的供体源性 CD8/CD4 同种反应性 T 细胞（除 CD44 记忆 T 细胞外）的百分比，并降低 HSCT 后早期的供体 T 细胞嵌合水平。我们的结果表明，PTCy 通过抑制 HSCT 后表达 PD-1 的供体源性 CD8/CD4 同种反应性 T 细胞，与 GVL 效应的损害和 GVHD 的改善相关。
