RAPAMYCIN, A POTENT IMMUNOSUPPRESSIVE DRUG FOR VASCULARIZED HEART, KIDNEY, AND SMALL-BOWEL TRANSPLANTATION IN THE RAT

The effectiveness of rapamycin (RAPA) was examined for heart, kidney, and small bowel allografts in rats. Untreated or vehicle only-infused Wistar Furth (RT1u) recipients rejected Buffalo (RT1b) heart allografts within a mean survival time (MST) of 6.5+/-0.5 and 6.3+/-0.5 days, respectively. In contrast, a 14-day continuous intravenous (i.v.) infusion by an osmotic pump of 0.08 mg/kg/day RAPA to WFu recipients prolonged BUF heart allograft survival to an MST of 34.4+/-12.1 days (P = 0.0001). There was a graded dose-response to 0.16 mg/kg (39.0+/-8.7 days; P = 0.0001), 0.32 mg/kg (55.7+/-3.3 days; P = 0.0001) and 0.8 mg/kg (48.0+/-3.6; P = 0.0001). Furthermore, intraarterial/intragraft but not i.v. infusion of 0.02 mg/kg/day prolonged BUF heart allografts-namely, an MST of 14.6+/-1.4 days versus 8.6+/-2.6 days (P = 0.0001), respectively. Local delivery doses of RAPA were about as effective as the same dose delivered i.v.: 0.08 mg/kg MST 37.0+/-18.3 days (P = 0.0001); 0.32 mg/kg, 40.0+/-3.9 days (P = 0.0001); and 0.8 mg/kg, 54.8+/-8.2 days (P = 0.0001). Systemic i.v. RAPA therapy with 0.08 or 0.8 mg/kg/day prolonged the survival of BUF kidney grafts in WFu recipients-namely, an MST of 52.7+/-42.7 (NS) and 90.2+/-62.4 (P = 0.001) days, respectively, versus an MST of 11.6+/-1.5 days in control WFu recipients only infused with vehicle. While normal WFu rats reject heterotopic BUF small bowel allografts within an MST of 10.0 days, a 14-day course of i.v. RAPA treatment significantly (P = 0.0001) prolonged small bowel allograft survival to an MST of 26.8+/-3.7 days.