title: FK-506 and methotrexate prevent graft-versus-host disease in dogs given 9.2 Gy total body irradiation and marrow grafts from unrelated dog leukocyte antigen-nonidentical donors.
abstract: FK-506 was evaluated either alone or combined with methotrexate (MTX) for prevention of graft-versus-host disease (GVHD) in dogs given 9.2 Gy total body irradiation and dog leukocyte antigen-nonidentical unrelated marrow grafts. Studies with marrow autografts showed gut toxicity and weight loss to be major side effects of FK-506. There was no hematopoietic toxicity with FK-506. In an initial allograft study, 5 dogs were given FK-506 intramuscularly at 0.3 mg/kg/day from days 0 to 8 and then orally at 0.5 mg/kg/day. All 5 died, 3 with intussusception most likely due to FK-506 toxicity, 1 with graft failure, and 1 with GVHD. Subsequently, the FK-506 dose was reduced and these drug schedules were used: FK-506 days 0-8 at 0.15 mg/kg/day i.m. and then orally at 0.5 mg/kg/day until day 90, with or without MTX intravenously at 0.4 mg/kg days 1, 3, 6, and 11. Twenty allografts were done, 10 with FK-506 alone, and 10 with MTX/FK-506. Results were compared with those in concurrent and historical controls given either no immunosuppression (n = 64), MTX (n = 114), CsA (n = 15), or MTX/CsA (n = 17). Five of 20 current dogs died with intussusception, too early to be evaluated for GVHD. The 10 dogs given FK-506 alone survived significantly better than those not given immunosuppression but not differently from those given short-term MTX or CsA alone. Three died from toxicity, 2 with graft failure, and 4 with GVHD. Only 1 dog became a long-term survivor, and this dog inadvertently received a single dose of MTX on day 7. Two of 10 dogs given MTX/FK-506 died from toxicity, 1 died with graft failure, 2 died with GVHD, and 5 became long-term survivors, a result that is significantly better than seen with either drug alone and similar to that seen with MTX/CsA. Four of the 5 survivors had no clinical GVHD. FK-506 blood levels were 15-35 ng/ml between days 8 and 15, when gut toxicity was most severe. Thereafter, levels were approximately 5 ng/ml. In conclusion, FK-506 prolonged survival of recipients of dog leukocyte antigen-nonidentical unrelated marrow grafts. When FK-506 was combined with MTX, graft-host tolerance was induced in 50% of dogs, even though FK-506 was stopped on day 90.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98104-2092.
authors.forename: R
authors.initials: R
authors.lastname: Storb
authors.forename: R F
authors.initials: RF
authors.lastname: Raff
authors.forename: F R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: H J
authors.initials: HJ
authors.lastname: Deeg
authors.forename: W
authors.initials: W
authors.lastname: Fitzsimmons
authors.forename: T C
authors.initials: TC
authors.lastname: Graham
authors.forename: M
authors.initials: M
authors.lastname: Pepe
authors.forename: M
authors.initials: M
authors.lastname: Pettinger
authors.forename: G
authors.initials: G
authors.lastname: Sale
authors.forename: R
authors.initials: R
authors.lastname: van der Jagt
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000473:pathology; D004285:Dogs; D006085:Graft Survival / Q000276:immunology*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006098:Granulocytes / Q000473:pathology; D006650:Histocompatibility Testing; D008727:Methotrexate / Q000627:therapeutic use*; D016559:Tacrolimus / Q000627:therapeutic use*; D014182:Transplantation, Autologous / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology; D014916:Whole-Body Irradiation
chemical_list: D016559:Tacrolimus; D008727:Methotrexate