Glucocorticoids fail to enhance the effect of FK506 and methotrexate in prevention of graft-versus-host disease after DLA-nonidentical, unrelated marrow transplantation.
Several steroid receptor-associated heat shock proteins can bind to FK506 as immunophilins. This has led to speculation that the steroid receptor and immunophilin signal transduction pathways are functionally interrelated. Indeed, in vitro work showed that FK506 treatment of intact L929 cells which were stably transfected with various reporter plasmids resulted in a potentiation of glucocorticoid hormone-induced glucocorticoid receptor-mediated gene transcription. These findings have raised the possibility of additive or synergistic immunosuppressive effects of FK506 and glucocorticoids. We tested this hypothesis in a canine model of GVHD prevention. Two groups of dogs were given 9.2 Gy total body irradiation followed by hematopoietic grafts from unrelated DLA-nonidentical donors. Among the first group of four recipients which were given FK506 and glucocorticoids, one rejected the graft, while three developed acute GVHD and died from associated complications between days 14 and 34. In the second group of nine recipients which were given FK506, glucocorticoids and methotrexate (MTX), only one dog became a long-term survivor while eight dogs died between days 21-114 with GVHD (n = 5) or FK506-associated toxicities (n = 3). Thus, addition of glucocorticoids to FK506 or FK506/MTX showed neither synergistic nor additive effects with respect to GVHD prevention in this model, and no survival advantages were seen compared to previously reported results with FK506 alone or FK506 and MTX in combination, respectively.
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Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98104-2092, USA.
Seidel
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Fitzsimmons
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Sale
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Storb
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D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D004285:Dogs; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use*; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use*
D005938:Glucocorticoids; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; C039692:histocompatibility antigen DLA; D016559:Tacrolimus; D008727:Methotrexate