RAPAMYCIN GRAFT PRETREATMENT IN SMALL-BOWEL AND KIDNEY-TRANSPLANTATION IN THE RAT

The effect of rapamycin (RAPA) as graft pretreatment was evaluated in orthotopic small bowel and kidney allotransplantation (Tx) in the rat. In the small bowel Tx model, six groups were involved, each including three combinations for evaluation of host-versus-graft (HVG) [Lewis ( LEW) x Brown Norway (BN) (LBN)-F-1 --> Lewis], graft-versus-host (GVH) (LEW --> F-1), and combined HVG and GVH immune responses (BN --> LEW) . RAPA graft pretreatment alone (16 mu g/ml x 3 ml) was able to induce a modest but significant prolongation of survival in all three combin ation models compared with controls (P<0.05). The same was observed fo r low dose CsA treatment (2 mg/kg/day x 14 days) of the recipient only (P<0.05). Combination of graft pretreatment with RAPA and CsA recipie nt treatment produced a marked prolongation of survival especially in HVG response. Recipients treatment with one 48-mu g bolus of RAPA i.v. immediately after graft revascularization failed to achieve any prolo ngation of survival for the GVH or combined HVG and GVH responses. Thi s seems to exclude a ''carryover'' effect of RAPA from graft to recipi ent. RAPA efficacy was also clearly confirmed in the kidney graft pret reatment model as compared to recipient treatment with an equivalent R APA dose. These results demonstrate that graft RAPA pretreatment prolo ngs SE survival after Tx in the rat for HVG, GVH, and bidirectional im mune responses. Intragraft interaction with passenger leukocytes or AP C function appears as one of the possible mechanisms. RAPA graft pretr eatment potentiates low dose CsA recipient treatment suggesting a poss ible use in clinical organ Tx.