Sensitivity of graft rejection in rats to local immunosuppressive therapy

In this study we investigated whether allograft rejection is sensitive to local immunosuppressive therapy. In rats, cardiac transplantations (BN----Lewis) were performed with venous return on the portal vein of the recipient. For local treatment the topical steroid budesonide was infused with an osmotic minipump directly into the carotid artery of the transplant. Budesonide is rapidly cleared by the liver, and cardiac tissue binding of the drug is high. Hence, local budesonide administration, 120 micrograms/kg/day, resulted in high drug levels within the graft (29.6 ng/mg) and low systemic drug levels (0.34 ng/ml). Systemic drug levels were so low that systemic biological effects of the drug during local administration were not measurable. In contrast systemic drug delivery, via the jugular vein of recipient, resulted in similar drug levels within the graft (31.0 ng/mg), but with high systemic drug levels within the graft (31.0 ng/mg), but with high systemic drug levels (1.65 ng/ml) and important systemic side effects. Both local and systemic administration of budesonide, 120 micrograms/kg/day for 13 days, resulted in significant prolongation of graft survival; median graft survival time was respectively 19.5 days and 20.0 days, compared with 7 days in controls. These results demonstrate that allograft rejection can be treated locally without significant systemic immunosuppression.