BUDESONIDE, A LOCALLY ACTING STEROID, PREVENTS GRAFT-REJECTION IN A RAT MODEL OF INTESTINAL TRANSPLANTATION

Background. The requirement for potent systemic immunosuppression to p revent intestinal graft rejection has resulted in high rates of infect ion and posttransplant lymphoproliferative disease. Budesonide (BUD) i s a locally acting steroid that is almost completely metabolized durin g its first pass through the intestinal wall and liver. The present st udy examined whether BUD could prevent small bowel allograft rejection without causing the adverse systemic effects associated with predniso lone. Methods. Orthotopic Brown Norway to Lewis rat small bowel allotr ansplants were randomly assigned to treatment with low-dose BUD (0.1 m g/kg/day, p.o.) and high-dose BUD (1.0 mg/kg/day, p.o.) with and witho ut cyclosporine (CsA; 2 mg/kg/day s.c.). The following parameters were assessed: allograft survival, recipient plasma adrenocorticotrophic h ormone (ACTH) levels, recipient adrenal, splenic and thymic weights, r ecipient CsA levels, and graft histopathology. Results. Low- and high- dose BUD alone did not prolong graft survival compared with the untrea ted group (9.1+/-0.4 days vs. 11+/-0.8 days vs. 9.7+/-0.4 days, respec tively), However, when low-dose BUD and high-dose BUD were given in co mbination with CsA, the mean graft survival times were prolonged to 27 .6+/-5.3 and 36.6+/-8.0 days, respectively (P < 0.01), ACTH levels, ad renal weights, and thymic weights were not significantly different in the treatment and control groups receiving intestinal transplants. Con clusions. BUD enhances the immunosuppressive effects of CsA and prolon gs small bowel allograft survival in rats without inhibiting normal AC TH release, These data suggest that BUD may be a useful immunosuppress ive agent for clinical intestinal transplantation.