Prevention of acute graft-vs-host disease by a single low-dose cyclophosphamide injection following allogeneic bone marrow transplantation

• Published in: Experimental hematology 2008-12, Vol.36 (12), p.1750-1759
• Main Authors: Prigozhina, Tatyana B, Elkin, Gregory, Khitrin, Sofia, Slavin, Shimon
• Format: Article
• Language: English
• Subjects: Acute Disease; Advanced Basic Science; Animals; Bone Marrow Transplantation; Cyclophosphamide - pharmacology; Graft Survival - drug effects; Graft Survival - radiation effects; Graft vs Host Disease - prevention & control; Graft vs Leukemia Effect - drug effects; Graft vs Leukemia Effect - radiation effects; Hematology, Oncology and Palliative Medicine; Mice; Mice, Inbred BALB C; Myeloablative Agonists - pharmacology; T-Lymphocytes; Transplantation Conditioning; Transplantation, Homologous; Whole-Body Irradiation
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2008.07.002

Objective Previously, we documented that conditioning based on donor-specific cell transfusion (DST) and subsequent selective depletion of activated donor-reactive cells by cyclophosphamide (CY) facilitates alloengraftment in a murine transplantation model. Transplantation event represents a strong immunogenic stimulus for host-reactive donor T cells that induce graft-vs-host disease (GVHD). Therefore, in this study, we addressed the question of whether a single posttransplantation CY administration (CY2 ) can prevent acute GVHD-related mortality without compromising engraftment of allogeneic transplant. Materials and Methods Splenocyte-enriched C57BL/6 bone marrow was transplanted to BALB/c recipients after mild irradiation, and conditioning with DST and 100 mg/kg CY. Following transplantation, recipients were left untreated or given on a specified day a single CY2 injection (50 mg/kg). All animals were monitored for survival, chimerism, and clinical signs of GVHD. Experimental mice that received BCL1 leukemia cells before transplantation were monitored for leukemia-related mortality as well. Results Animals that received no CY2 after transplantation died of acute GVHD. A single low-dose CY2 treatment within the first 5 days after transplantation prevented mortality in most recipients. However, only CY2 administration on days +1 or +5 preserved chimerism. Most chimeras survived GVHD-free for >200 days. Prolonged persistence of host-reactive T cells in mice (CY2 on day +5) permitted a reduction to be made in engraftment-essential irradiation dose and preserved a strong graft-vs-leukemia effect of transplantation. Conclusion Acute GVHD can be prevented in mice by a single properly timed posttransplantation low-dose CY administration.