EFFICACY OF RAPAMYCIN AND FK-506 IN PROLONGING RAT HIND-LIMB ALLOGRAFT SURVIVAL

Objective Graft rejection and the toxicity of current immunosuppressiv e regimens preclude the application of microsurgical advances to trans plantation of limbs or other nonessential parts. If limb transplantati on is to become a clinical reality, newer, safer, more effective immun osuppressive agents are needed. Summary Background Data Rapamycin (RPM ) and FK 506 are fungal macrolide antibiotics with effective immunosup pressive properties demonstrated in several animal models. RPM is more potent and effective than is FK 506 in rat cardiac allografts and has demonstrated synergy with cyclosporine (CsA) in limb allograft models . Methods An orthotopic rat hind limb allograft model (Brown-Norway [R T-1(n)] to Lewis [RT-1(1)] rats was used. RPM (doses, 3.0, 4.5, and 6. 0 mg/kg/day) was administered intraperitoneally on postoperative days 1 to 14. FK 506 (6 mg/kg/day) was administered orally on postoperative 1 to 14 and 1 to 90 and at rejection onset(10 mg/kg/day for salvage). CsA with RPM (postoperative days 1 to 14) was used to assess synergy, with CsA alone serving as the control. Other controls included untrea ted and placebo-treated allografted animals. The permutation test and Mann-Whitney test were applied to the data. Results The mean survival times were assessed as follows. (1) control (placebo, untreated), 5 da ys; (2) RPM groups, 9.5, 10.6, and 8.7 days; (3) 14-day FK 506, 28 day s; (4) 90-day FK 506, >90 days; (5) CsA, 17.3 days; and (6) CsA with R PM, 19.3 days. FK 506 significantly prolonged graft survival compared with RPM (Permutation Test, p<0.001 and Mann-Whitney Test, p<0.05). FK 506 salvage reversed early rejection. High-dose RPM produced signific ant toxicity. Synergy between CsA and RPM was not demonstrated. Conclu sions FK 506 prolongs allograft survival, reverses early rejection, an d prevents rejection without clinical toxicity when given continually. RPM does not prevent rejection in this model and produces significant toxicity at high doses. FK 506 may be a first step in making limb tra nsplantation a clinical reality in reconstructive surgery.