A murine model of NKT cell-mediated liver injury induced by alpha-galactosylceramide/ d -galactosamine

Natural killer-T (NKT) cells are rich in the liver. However, their involvement in liver injury is not fully understood. We developed here a new murine model of NKT-cell-activation-associated liver injury, and investigated a role of tumor necrosis factor alpha (TNF-α) and Fas in pathogenesis. We injected intraperitoneally alpha-galactosylceramide (α-GalCer), an NKT-cell stimulant, into d -galactosamine (GalN)-sensitized mice. Survival rate, pathological changes of the liver, and plasma concentrations of cytokines were studied. Alpha-GalCer/GalN administration gave a lethal effect within 7 h, making pathological changes such as massive parenchymal hemorrhage, hepatocyte apoptosis, sinusoidal endothelial cell injury, and close apposition of lymphocytes to apoptotic hepatocytes. Anti-NK1.1 mAb-pretreated mice and Vα14NKT knock out (KO) mice did not develop liver injury. Tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) were elevated at 4 h in the plasma. These cytokines were produced by hepatic lymphocytes as demonstrated by in vitro stimulation with α-GalCer. The lethal effect was suppressed in TNF-α KO mice, TNF receptor-1 KO mice, and lpr/lpr (Fas deficient) mice, whereas it was not in IFN-γ KO mice. These results indicate that the present liver injury is characterized by parenchymal hemorrhage and hepatocyte apoptosis, and mediated by TNF-α secretion and direct cytotoxicity of α-GalCer-activated NKT cells.