Posttransplantation cyclophosphamide facilitates engraftment of major histocompatibility complex-identical allogeneic marrow in mice conditioned with low-dose total body irradiation

Abstract

Cyclophosphamide (Cy) has been studied extensively for its immunosuppressive properties and is frequently combined with total body irradiation (TBI) as conditioning prior to HLA-identical allogeneic blood or marrow transplantation (alloBMT) in humans. Because Cy is most effective at suppressing host-versus-graft reactions when the drug is given after the transplantation (Mayumi H et al. Transplant Proc. 1986;18:363-369), we investigated whether posttransplantation Cy could prevent rejection of allogeneic marrow in mice conditioned with low-dose TBI. In a mouse model, posttransplantation Cy reduced the dose of TBI required from 500 cGy to < or = 200 cGy for the engraftment of 10 million major histocompatibility complex (MHC)-identical marrow cells in 100% of recipients. In animals conditioned with low-dose TBI and posttransplantation Cy, donor chimerism was proportional to the dose of TBI, was present in multiple hematopoietic lineages, and was associated with the indefinite survival of donor-strain skin grafts. In contrast, animals conditioned with either TBI alone or posttransplantation Cy alone failed to achieve engraftment after alloBMT and contained antidonor cytotoxic T-cells. Although <5% donor chimerism could be induced without TBI by transplanting > or = 50 million MHC-identical cells and administering posttransplantation Cy, the addition of low-dose TBI reduced the dose of donor cells required for alloengraftment and increased long-term donor chimerism to >50%. These data demonstrate that low-dose TBI and posttransplantation Cy cooperate to prevent graft rejection following the transplantation of standard doses of MHC-identical marrow cells.