INTRAPORTAL DELIVERY OF IMMUNOSUPPRESSION TO INTRAHEPATIC ISLET ALLOGRAFT RECIPIENTS

Local delivery of immunosuppressive agents may dampen local alloreacti ve events with avoidance of systemic toxicity. We investigated the inn ovative strategy of intraportal (IPO) delivery of three immunosuppress ive agents in streptozotocin diabetic rat recipients of islet allograf ts (Lewis to Wistar-Furth) transplanted intrahepatically. IPO budesoni de (BUD, 240 or 360 mu g/kg per day), a potent steroid, and cyclospori n (CyA, 2 or 4 mg/kg per day) did not prolong graft mean survival time [MST +/- standard deviation (SD)] as compared to nonimmunosuppressed recipients. Fourteen days of IPO FK 506 (0.16 mg/kg per day) significa ntly increased MST as compared with untreated controls (49 +/- 29 vs 7 +/- 1 days, P < 0.01) and was more effective than intravenous (IV) FK 506 (17 +/- 7 days, P < 0.01). When FK 506 was given for 28 days, the benefit of IPO over IV delivery was reaffirmed (MST 81 +/- 32 vs 34 /- 4 days, P < 0.01). The potential for toxicity was lessened by lower mean systemic levels in the IPO group as compared to the IV group (1. 3 +/- 0.6 vs 3.5 +/- 0.9 ng/mg, P < 0.02). The strategy of continuous IPO FK 506 was effective in the prevention of rejection of intrahepati c islet allografts.