The effect of donor-specific blood transfusion, cyclosporine, and dietary prostaglandin precursors on rat cardiac allograft survival. II. Effectiveness of a 24-hour induction period with DST and CsA in inducing long-term graft survival.

Abstract

We investigated the effect of donor-specific transfusion given 24 hours pretransplant, a short course of low-dose cyclosporine, and dietary enrichment with the prostaglandin precursor linoleic acid (LA) to see which of the modalities could act synergistically on cardiac allograft survival in a stringent animal model. ACI male rats (RT1a) were used as blood and heart donors, and Lewis male rats (RT1l) were used as recipients. DST alone (1 ml) given 24 hr pretransplant or LA alone started 24 hr pretransplant and given daily p.o. until rejection prolonged cardiac allograft survival slightly but significantly, from 6 to 8 days. CsA alone started at the time of transplant at a dose of 5 mg/kg/day s.c. and given daily for 14 days prolonged cardiac survival to 11.8 days. However, when CsA was started 24 hr pretransplant and continued for two weeks, there was a significantly prolonged allograft survival to 55 days. CsA given together with DST 24 hr pretransplant and continued for two weeks posttransplant significantly prolonged cardiac allograft survival to 80 days and resulted in permanent tolerance in some animals. The addition of LA to a DST and CSA treatment regimen did not further improve allograft survival. CsA blood levels were determined in a separate group of Lewis rats. Three dosages of CsA were administered s.c. for 2 weeks: 2.5 mg/kg/day, 5 mg/kg/day, and 10 mg/kg/day. One injection of the three CsA doses did not achieve what are considered therapeutic levels in man. After 5 days, all three doses of CsA achieved significant blood levels. Significant blood levels were still present one week, but not 3 weeks after CsA was stopped. We conclude that DST given 24 hr before transplant and a 2-week course of low-dose CsA started one day pretransplant have strong synergism in inducing long-term graft survival in this rat model. Linoleic acid started 24 hr pretransplant, together with DST and CsA, did not contribute significantly to graft survival compared with the group given CsA and DST alone. Prolonged heart allograft survival was not due to persistently high CsA levels after the drug was discontinued.