EVIDENCE THAT RAPAMYCIN RESCUE THERAPY DELAYS REJECTION OF MAJOR (MHC) PLUS MINOR (NON-MHC) HISTOINCOMPATIBLE HEART ALLOGRAFTS IN RATS

The capacity of delayed onset of rapamycin (RAPA) therapy to block process of destruction was examined in rats undergoing heart allograft rejection. Untreated Wistar Furth (WFu; RT-1u) recipients reject Buffalo (BUF; RT-1b) heart allograft with a mean survival time (MST) of 6.5+/-0.5 days. A 14-day i.v. infusion of 0.8 mg/kg RAPA begun on the day of transplantation prolonged the survival to 74.1+/-20.2 days (P<0.001), 0.2 mg/kg to 32.2+/-10.0 days (P<0.001), and 0.08 mg/kg to 36.4+/-11.8 days (P<0.001). When RAPA therapy (0.8 mg/kg) was begun 3 or 4 days after transplantation, the grafts survived 85.2+/-31.1 (P<0.001), and 70.2+/-43.3 (P<0.005) days, respectively. Therapy initiated on day 5 was much less effective; most transplants were rejected within 10 days; one graft survived 32 and two grafts 60 days (MST = 17.6+/-20.0, NS). A 0.2 mg/kg RAPA dose prolonged graft survival with initial use on days 3 (31.6+/-12.2 days; P<0.001) or 4 (31.4+/-8.1 days; P<0.001) but not on day 5. The 0.08 mg/kg RAPA prolonged hearts only when started on day 3 (47.2+/-2.7 days; P<0.001) but not on days 4 or 5. WFu recipients treated with a subtherapeutic dose of cyclosporine (1 mg/kg; 9.1+/-1.5 days) displayed prolonged heart allograft function when treated subsequently with RAPA (0.8 or 0.08) beginning from days 4, 5, or 6 postgrafting. These in vivo results are supported by in vitro experiments. The frequency of BUF alloreactive elements among normal WFu LN cells (fTc) was 337+/-139/10(6) T cells in limiting dilution assay. Addition of RAPA (1 muMol) at the beginning of culture significantly reduced (P<0.025) the fTc to 17+/-6.6/10(6) or alternatively on days 4 or 6 to 37.3+/-20.0/10(6) and 58.6+/-21.8/10(6), respectively. Thus, both in vivo and in vitro data demonstrate that delayed RAPA therapy may interrupt alloimmune reactions.