REVERSAL OF ONGOING HEART, KIDNEY, AND PANCREAS ALLOGRAFT-REJECTION AND SUPPRESSION OF ACCELERATED HEART ALLOGRAFT-REJECTION IN THE RAT BY RAPAMYCIN

Rapamycin was examined for its effects on reversal of ongoing rejectio n of heart, kidney, and pancreas allografts and on suppression of acce lerated heart allograft rejection in the rat. A 14-day continuous intr avenous infusion of RAPA by an osmotic pump at 0.02, 0.08, and 0.8 mg/ kg/day to WFu recipients, starting 4 days postoperation, significantly protected the BUF heart allografts with a mean survival time (MST) +/ - 1 SD of 33.2+/-19.8 (p<0.001), 48.2+/-14.8 (p<0.001), and 107.0+/-86 .3 (p<0.001) days, respectively, as compared with 7.2+/-0.8 days in ve hicle-treated controls. Combination of low dose RAPA (0.02 mg/kg or 0. 08 mg/kg) and low dose CsA (2 mg/kg) achieved significantly longer car diac allograft survival than RAPA or CsA alone. RAPA's effect in rever sing ongoing rejection of renal and pancreatic allografts was also sig nificant. The BUF kidney and pancreas in WFu recipients treated with a 14-day course of RAPA (0.8 mg/kg/day starting 4 days postoperation) h ad an MST of 44.7+/-15.9 (p<0.001) and 46.4+/-12.5 days (p<0.001), whi le in vehicle-treated controls, the grafts were rejected within 10 day s. RAPA could also suppress accelerated cardiac allograft rejection. H yperimmunized WFu recipients were treated with two 14-day courses of c ontinuous i.v. RAPA at 0.8 mg/kg/day before and after BUF heart allogr afting. Significantly longer survival of the grafts (25.5+/-3.7 days, p<0.001) was achieved compared with that of the vehicle-treated contro ls (3.8+/-1.0 days). One-course RAPA treatment before or after heart t ransplantation was considerably less effective. RAPA was also shown to prevent the increase of serum IgG levels and to inhibit the productio n of specific cytotoxic Ab in the rat receiving repetitive immunizatio ns. Such effects presumably contribute to the inhibition of the accele rated rejection. The results of this study suggest that RAPA is potent ially useful in treatment of ongoing as well as accelerated allograft rejection.