90 CYCLOSPORINE AND TACROLIMUS HAVE DIFFERENT INHIBITORY EFFECTS ON TOLL-LIKE RECEPTOR SIGNALLING IN HEPATITIS C RECURRENCE POST LIVER TRANSPLANTATION

Abstract

Background and Aims: Ischemia-reperfusion injury (IRI) is a key factor that contributes to early and late dysfunction of liver grafts. Recent studies reveal that natural killer (NK) cells play an important role in liver injury post IRI. We hypothesized that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand with high expression on NK cells significantly impacts IRI. Methods: C57/BL6 wild-type and TRAIL knock-out mice (TRAIL−/−) were subjected to hepatic IRI for one hour. Adoptive transfer of wild-type and TRAIL−/− NK cells was performed into RAG2/common gamma null mice that lack T, B and NK cells. Liver injury was assessed by hepatic neutrophil infiltration, alanine aminotransferase (ALT), aspartate transaminase (AST), hepatic neutrophil activation by myeloperoxidase (MPO) activity. NK cell subsets of the ischemic liver lobe were analysed by flow cytometry. NK cell cytotoxicity and interferon gamma secretion were performed in vitro studies. Results: TRAIL−/− mice exhibit significantly more hepatic damage assessed by AST and ALT levels 24 hours post IRI compared to wildtype mice. Adoptive transfer of TRAIL−/− NK cells to Rag2/common gamma-null mice was associated with significantly increased IRI compared to transfer with wild-type NK cells. Hepatic neutrophil activation was significantly increased in TRAIL−/− compared to wild-type mice. Staining for CD107a, a marker of degranulation and cytotoxicity on NK cells was significantly elevated in ischemic liver lobes of TRAIL−/− compared to wild-type mice. In vitro NK cell cytotoxicity to a Yac-1 cancer cell line was significantly increased in sorted TRAIL−/− NK cells compared to wild-type NK cells. Systemic cytokine levels (TNF alpha, IL-1beta, IL-6) and interferon gamma secretion of NK cells after stimulation with IL-12/IL-18 in vitro were not significantly different between the groups. Conclusions: These results show that expression of TRAIL on NK cells is protective in a murine model of hepatic IRI via the modulation of NK cell mediated cytotoxicity.