MECHANISMS OF TOLERANCE TO RAT-HEART ALLOGRAFTS USING POSTTRANSPLANT TLI - CHANGES IN CYTOKINE EXPRESSION

Lewis rats were rendered tolerant to ACI heart allografts using a regi men of posttransplant total lymphoid irradiation (TLI), rabbit antithy mocyte or antilymphocyte globulin (RATG or RALG), and a single donor b lood transfusion. All three treatment modalities were required to indu ce tolerance. The mechanism of the maintenance of tolerance was invest igated by comparing the secretion of cytokines in the MLR, and the exp ression of cytokine mRNA in the allografts of tolerant and nontolerant Lewis rats. Although, the H-3-thymidine incorporation and secretion o f IL-2 was frequently comparable in the MLR from tolerant and nontoler ant rats, the secretion of IFN-gamma was markedly reduced in the toler ant rats. This was reflected in a markedly reduced frequency of cells expressing IFN-gamma mRNA in the allografts of tolerant as compared wi th nontolerant hosts, The frequency of cells expressing IL-2 and IL-10 mRNA was also reduced, but no significant difference was observed for cells with IL-4 mRNA. Spleen cells from nontolerant rats rapidly reje cted ACI allografts in irradiated adoptive hosts, but spleen cells fro m tolerant rats did not. Evaluation of the cytokine mRNA expression at early and late time points in the allografts of adoptive hosts showed a pattern similar to that of the primary hosts. Thus, the tolerant st ate was associated With a maintenance or elevation of IL-4 expression and a marked reduction of IFN-gamma expression, Previous reports have shown that TLI alone induced this shift in the early recovery phase af ter irradiation.