Posttransplantation cyclophosphamide facilitates engraftment of major histocompatibility complex-identical allogeneic marrow in mice conditioned with low-dose total body irradiation.
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.
Luznik
Leo
L
Division of Immunology/Hematopoiesis, Johns Hopkins Oncology Center, Baltimore, Maryland, USA.
Engstrom
Laura Wendy
LW
Iannone
Robert
R
Fuchs
Ephraim Joseph
EJ
D000818:Animals; D002452:Cell Count; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D006085:Graft Survival / Q000187:drug effects*; D006648:Histocompatibility; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016038:Skin Transplantation / Q000379:methods; D033581:Stem Cell Transplantation / Q000379:methods*; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014185:Transplantation, Isogeneic / Q000379:methods; D014916:Whole-Body Irradiation
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide