Liver allografts are not rejected in the fully incompatible Lewis-RT11 (LEW) to blood group D Agouti-RT1a (DA) rat strain combination despite an early infiltration by recipient mononucleated cells that initially display a phenotype, an ability to respond to interleukin-2 (IL-2) and donor-specific cytotoxicity indistinguishable from that observed in the rejected, DA to LEW combination. To further analyze the mechanism of this tolerance, we have compared in these two combinations, as well as in syngeneic grafts and in normal livers, the presence of intrahepatic cytokine transcripts (IL-1α, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor [TNF]-α, TNF-β, and transforming growth factor [TGF]-β) by a semiquantitative polymerase chain reaction (PCR) or by northern-blotting. In normal livers or syngeneic grafts, IL-1α, TNF-β, and TGF-β were the only cytokines detected by these methods. The levels of all cytokine transcripts were increased in allogeneic grafts. Expression of cytokine transcripts was very similar in the two allogeneic strain combinations except IL-4, which was expressed at a much lower level in the nonrejected strain than in the rejected strain from day 2 onward. We conclude that selective downregulation of IL-4 gene expression is associated with, and a potential mediator of, the induction of tolernce in this model.