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.

Yosuke Makuuchi, Yasuhiro Nakashima, Mitsutaka Nishimoto, Hideo Koh, Masayuki Hino, Hirohisa Nakamae

Experimental hematology 2023 Jul

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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. Copyright © 2023 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Citation

Yosuke Makuuchi, Yasuhiro Nakashima, Mitsutaka Nishimoto, Hideo Koh, Masayuki Hino, Hirohisa Nakamae. 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. Experimental hematology. 2023 Jul;123:56-65