TOLERANCE TO CARDIAC ALLOGRAFTS REQUIRES A TIME-LAG BETWEEN INTRATHYMIC TREATMENT AND TRANSPLANTATION

Permanent tolerance to an experimental heterotopic cardiac allograft c an be achieved by pretreatment with antilymphocyte serum (ALS) and int rathymic inoculation of donor cells. Most successful experimental prot ocols have employed a time lag of 2 to 3 weeks between intrathymic pre treatment and transplantation, which makes this treatment strategy imp ractical for clinical heart transplantation. In these experiments we m odified the standard protocol by giving ALS 24 hr prior to both intrat hymic injection of donor cells and heterotopic transplantation. Seven Lewis rats had intraperitoneal injection of 1 ml of ALS and 24 hr late r underwent intrathymic injection of 5 x 10(7) donor Lewis-Brown Norwa y (LBN) splenocytes and heterotopic cardiac transplantation using an L BN donor. Mean graft survival was 24.4 days, significantly longer than the 7.8-day graft survival observed in untreated Lewis recipients (n = 5) (P < 0.02). However, graft survival was not different from that o bserved in Lewis rats pretreated with ALS alone (n = 5) (25.8 days, P = NS). Permanent graft survival was produced in two rats receiving onl y ALS and in one rat receiving both ALS and intrathymic inoculation. I n these experiments it appears that prolongation of graft survival may have been due to the effect of ALS alone. These results suggest that there is a critical time period between intrathymic inoculation and tr ansplantation that is needed for permanent tolerance to be induced con sistently. This may be due to the kinetics of the effects of ALS on al loreactive T-lymphocytes or to a time-dependent requirement for antige n processing in the thymus. (C) 1996 Academic Press, Inc.