移植后的环磷酰胺通过抑制异种反应性T细胞、有助于改善移植物抗寄生白血病效应和缓解移植物抗宿主病,这是在小鼠干细胞移植模型中的结果。
Posttransplant cyclophosphamide contributes to the impairment of the graft-versus-leukemia effect and the amelioration of graft-versus-host disease with the suppression of alloreactive T cells in a murine stem cell transplant model.
发表日期:2023 Apr 23
作者:
Yosuke Makuuchi, Yasuhiro Nakashima, Mitsutaka Nishimoto, Hideo Koh, Masayuki Hino, Hirohisa Nakamae
来源:
Experimental Hematology & Oncology
摘要:
移植后环磷酰胺(PTCy)是靠抑制供体来源的异反应性T细胞在同种异基因造血干细胞移植(HSCT)中预防移植物抗宿主病(GVHD)的有效预防方法。移植物抗白血病效应(GVL)是由供体来源的异反应性T细胞诱导的抗白血病效应,类似于GVHD,然而,没有研究证明PTCy后供体来源的异反应性T细胞动态与HSCT后GVL效应受损之间的关联。我们在小鼠HSCT模型中评估了带有功能标记的细胞死亡程序-1(PD-1)的供体来源T细胞的动态。我们显示PTCy与造血干细胞移植模型中的白血病细胞的发展和生存概率下降相关,而在没有白血病细胞的造血干细胞移植模型中,PTCy可以改善GVHD并提高生存概率。我们揭示了供体来源CD8+/CD4+异反应性T细胞中表达PD-1功能标记的细胞的百分比在接受者脾脏中被PTCy抑制,CD44+记忆T细胞除外,并且在PTCy后早期供体T细胞嵌合水平降低。我们的结果表明,PTCy通过抑制HSCT后表达PD-1的供体来源CD8+/CD4+异反应性T细胞来影响GVL效应和改善GVHD。版权所有©2023 Elsevier Inc.
Posttransplant cyclophosphamide (PTCy) is 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 anti-leukemia effect induced by donor-derived alloreactive T cells, similarly 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, while 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 suggested 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.Copyright © 2023. Published by Elsevier Inc.