Liver allografts are vigorously rejected in 9-12 days in Lewis recipients of fully histoincompatible DA livers. The purpose of this study was to examine the initial events in this cascade, specifically the role of CD4+ T helper cells. Lewis recipients of DA or Lewis livers were killed at days 1, 2, 3, 4, and 7 days after transplant. Indicators of acute liver rejection, including a marked inflammatory infiltrate and decreased liver function, progressed in untreated recipients of allografts. Splenocytes taken from allogeneic recipients on days 1-4 and 7 proliferated in response to donor and third-party stimulators, whereas graft-infiltrating cells did not respond to donor and third-party antigens until day 3 after transplant, but thereafter maintained a good response. To further characterize the host T helper cell response to liver allografts, cytokine expression was analyzed in graft tissue and in the periphery. IL-4 mRNA was present in both syngeneic and allogeneic liver grafts, while message for IL-10 was present early in all liver grafts but persisted only in allografts. In contrast, IL-2 and IFN-gamma transcripts were specific to rejecting allografts. Similar patterns of cytokine expression were observed in the spleen, indicating the immune response to the graft involves the peripheral lymphoid organs. Thus, the cytokine profile detected during liver allograft rejection is extremely similar to that observed in other experimental models of transplantation.