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 FK 506 as immunophilins. This has led to speculation that the steroid rec eptor and immunophilin signal transduction pathways are functionally i nterrelated, Indeed, in vitro work showed that FK506 treatment of inta ct L929 cells which were stably transfected with various reporter plas mids resulted in a potentiation of glucocorticoid hormone-induced gluc ocorticoid receptor-mediated gene transcription, These findings have r aised the possibility of additive or synergistic immunosuppressive eff ects of FK506 and glucocorticoids, We tested this hypothesis in a cani ne model of GVHD prevention, Two groups of dogs were given 9.2 Gy tota l body irradiation followed by hematopoietic grafts from unrelated DLA -nonidentical donors, Among the first group of four recipients which w ere given FK506 and glucocorticoids, one rejected the graft, while thr ee developed acute GVHD and died from associated complications between days 14 and 34, In the second group of nine recipients which were giv en FK506, glucocorticoids and methotrexate (MTX), only one dog became a long-term survivor while eight dogs died between days 21-114 with GV HD (n = 5) or FK506-associated toxicities (n = 3), Thus, addition of g lucocorticoids to FK506 or FK506/MTX showed neither synergistic nor ad ditive effects with respect to GVHD prevention in this model, and no s urvival advantages were seen compared to previously reported results w ith FK506 alone or FK506 and MTX in combination, respectively.