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Clinical evidence suggests that many cases of serious idiosyncratic drug-induced liver injury (I-DILI) are mediated by the adaptive immune system in response to hepatic drug-protein adducts, also referred to as drug-induced allergic hepatitis (DIAH), but detailed mechanistic proof has remained elusive due to the lack of animal models. We have hypothesized that DIAH is as rare in animals as it is in humans due at least in part to the tolerogenic nature of the liver. Herein we provide evidence that immune tolerance can be overcome in a murine model of halothane-induced liver injury initiated by trifluoroacetylated protein adducts (TFAPA) of halothane formed in the liver. Twenty-four hours after female Balb/cJ mice were initially treated with halothane, perivenous necrosis and an infiltration of CD11b
+
Gr-1
high
cells were observed in the liver. Further study revealed a subpopulation of myeloid-derived suppressor cells (MDSCs) within the CD11b
+
Gr-1
high
cell fraction, that inhibited the proliferation of both CD4
+
and CD8
+
T cells. When CD11b
+
Gr-1
high
cells were depleted from the liver with Gr-1 antibody treatment, enhanced liver injury was observed at nine days after halothane rechallenge. Toxicity was associated with increased serum levels of IL-4 and immunoglobulins (Ig) IgG1 and IgE directed against hepatic TFAPA, as well as increased hepatic infiltration of eosinophils and CD4
+
T cells, all features of an allergic reaction. When hepatic CD4
+
T cells were depleted 5 days after halothane rechallenge, TFAPA-specific serum Ig and hepatotoxicity were reduced.