EXPRESSION OF CYTOKINES AND IMMUNE MEDIATORS DURING CHRONIC LIVER ALLOGRAFT-REJECTION

To determine the immune processes involved in chronic liver allograft rejection (CR) we examined in situ cytokine production in tissue from 15 patients with both clinical and histopathological diagnoses of CR. Total RNA was isolated from liver samples, reverse-transcribed and ana lyzed by RT-PCR for the production of proinflammatory cytokines and im munoregulatory mediators. Transcripts for the Th1-like cytokines IL-2 and IFN-gamma were detected in 53.3% and 46.7% of CR grafts, while the y were detected in only 16% and 0% of stable grafts, respectively. The cytotoxic T cell mediator granzyme B was expressed in the majority of liver grafts undergoing CR, but was expressed only in a minority of s table grafts (80% vs. 16%, P<0.05). The T cell product IL-5 was also s ignificantly upregulated in CR as compared with stable livers (80% vs. 16%, P<0.01). Other Th2 cytokines-IL-4 and IL-10-and macrophage produ cts-IL-1 beta, IL-6, IL-8, TGF-beta, and TNF-alpha-were not substantia lly upregulated in CR grafts as compared with stable grafts. PDGF-beta transcripts were detected in the majority of the CR grafts, but were not detected in stable liver grafts (73% vs. 0, P<0.05). By immunohist ochemical staining, we observed that CD3(+)CD4(+), and CD3(+)CD4(-) T cells were detected in CR grafts along with CD20(+) B cells and CD68() macrophages. There was, however, a predominant infiltration of CD3()CD4(+) lymphocytes. Taken together, these data suggest that infiltrat ing cells produce proinflammatory and immunoregulatory cytokines that have a role in mediating graft damage in CR.