Ex vivo treatment of murine splenocyte-supplemented bone marrow inocula with mafosfamide prior to allogeneic transplantation in an attempt to prevent lethal graft-versus-host disease without compromising engraftment.
Murine splenocyte-supplemented bone marrow cell suspensions were incubated with mafosfamide, an analog of "activated" cyclophosphamide, prior to transplantation across major histocompatibility barriers into lethally-irradiated recipient mice in an attempt to reduce the incidence of graft-versus-host disease (GvHD)-related mortality without compromising engraftment. Irradiated mice that received vehicle-treated splenocyte-supplemented bone marrow inocula developed symptoms of severe GvHD; the majority of such animals did not survive. Treatment of donor cells with 160 microM mafosfamide for 30 min resulted in a marked increase in animal survival without evidence of GvHD. Survival of bone marrow allografts was demonstrated by the persistence of donor-type mononuclear cells in the peripheral blood of surviving animals. Treatment of donor cells with a four-fold higher concentration of mafosfamide also resulted in a significant increase in survival without evidence of GvHD; however, host resistance to engraftment was indicated by a low percentage of donor mononuclear cells in the peripheral blood of the survivors. Treatment of donor cells with a four-fold lower concentration of mafosfamide resulted in a slight increase in survival; however, all animals developed symptoms of GvHD. These results indicate that, at appropriate concentrations, mafosfamide can effect the elimination of GvHD-causing T lymphocytes from donor bone marrow inocula without compromising its engraftment potential.
Kohn
F R
FR
Department of Pharmacology, University of Minnesota, Minneapolis 55455.
Sladek
N E
NE
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D016026:Bone Marrow Transplantation; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects; D006086:Graft vs Host Disease / Q000517:prevention & control*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation
C048341:mafosfamide; D003520:Cyclophosphamide