PERIPHERAL TOLERANCE OF AN ALLOGRAFT IN ADULT-RATS - CHARACTERIZATION BY LOW INTERLEUKIN-2 AND INTERFERON-GAMMA MESSENGER-RNA LEVELS AND BY STRONG ACCUMULATION OF MAJOR HISTOCOMPATIBILITY COMPLEX TRANSCRIPTS IN THE GRAFT

Congenic LEW.1W(RT1.u) heart grafts in LEW.1A(RT1.a) recipient rats are rejected in 15+/-6 days. Tolerance(>100 days) can be induced by pretransplant donor-specific blood transfusion. In this case, the graft is not rejected, although it is infiltrated by mononuclear cells specifically cytotoxic, in vitro, against allogeneic donor splenocytes. We studied the expression of MHC class I and class II antigens, IFN-gamma, and IL-2 mRNA in the rejected and tolerated grafts by Northern blotting and in situ hybridization. Our data show that both class I and class II mRNA accumulate in both types of graft, and that class I mRNA accumulation occurs more rapidly in the tolerated grafts. IFN-gamma and IL-2 mRNA accumulate to lower levels and with delayed kinetics in the tolerated grafts compared with the rejected ones, suggesting a role for these lymphokines in the mechanism of rejection/tolerance in this model. This hypothesis is also supported by the observation that IFN-gamma treatment abrogates the induction of tolerance in the recipients receiving pretransplant donor blood transfusion. Furthermore, we observed an uncoupling of the accumulation of IFN-gamma mRNA and of MHC class I and class II mRNA. Our data confirm that the mechanisms of tolerance in this model depend, in part, on alterations of the IL-2/IL-2R pathway of lymphocyte activation but also clearly indicate a decrease of IFN-gamma mRNA accumulation, suggesting that the defect involves several activation molecules.