Prolongation of rat skin and cardiac allograft survival by low molecular weight heparin

Back ground. We have previously reported that very low doses of low molecul ar weight heparin compounds (LMWH) inhibit a variety of T-cell-mediated rea ctions by down-regulation of TNF-alpha production. This study tested the ef ficacy of LMWH in organ transplantation. Methods. Skin and heterotopic heart transplantations were performed between recipient Wistar rats and donor BN rats. Two doses of LMWH were given sc, 1 and 20 mu g, each in three protocols, with day of grafting as Day 0: (A) Daily: -1, 0, 1. . . , (B) Late Weekly: -1, 6, 13 . . . , and (C) Early Wee kly: -7, 0, 7. . . . Doses and schedules were selected based on efficacy in autoimmune models. Skin graft rejection was defined by complete separation of the graft, and heart transplant rejection was defined as cessation of h eartbeat. Results. Treatment with 1 mu g (26.8 +/- 2.0 days) and 20 mu g (24.5 +/- 2. 3 days) of LMWH using the Early Weekly protocol significantly prolonged ski n allograft survival compared to controls (17.8 +/- 4.4 days), P < 0.001 fo r both, whereas other protocols did not. Compared to controls (8.3 +/- 1.4 days), treatment with both 1 and 20 mu g of LMWH using all three protocols significantly prolonged cardiac allograft survival. The efficacy, however, varied considerably. Increase in graft survival ranged from 18% (1 mu g, Da ily, 9.8 +/- 0.7 days, P = 0.02) to more than twofold (20 mu g, Early Weekl y, 20.8 +/- 5.5 days, P < 0.001) according to the dose and schedule of LMWH . Conclusions. Treatment with very low doses of non-anticoagulant LMWH prepar ations having anti-TNF-alpha activity significantly prolongs rat skin and c ardiac allograft survival in a dose- and schedule-dependent manner. (C) 199 9 Academic Press.