title: Drug-induced allergic hepatitis develops in mice when myeloid-derived suppressor cells are depleted prior to halothane treatment.
abstract: Clinical evidence suggests that many cases of serious idiosyncratic drug-induced liver injury are mediated by the adaptive immune system in response to hepatic drug-protein adducts, also referred to as "drug-induced allergic hepatitis"; but detailed mechanistic proof has remained elusive due to the lack of animal models. We have hypothesized that drug-induced allergic hepatitis is as rare in animals as it is in humans due at least in part to the tolerogenic nature of the liver. We provide evidence that immune tolerance can be overcome in a murine model of halothane-induced liver injury initiated by trifluoroacetylated protein adducts 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 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 9 days after halothane rechallenge. Toxicity was associated with increased serum levels of interleukin-4 and immunoglobulins G1 and E directed against hepatic trifluoroacetylated protein adducts, 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, trifluoroacetylated protein adduct-specific serum immunoglobulin and hepatotoxicity were reduced.
  
  
  CONCLUSIONS
  Our data provide a rational approach for developing animal models of drug-induced allergic hepatitis mediated by the adaptive immune system and suggest that impaired liver tolerance may predispose patients to this disease.
authors.affiliation: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Mala
authors.initials: M
authors.lastname: Chakraborty
authors.affiliation: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Fullerton
authors.affiliation: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Kenrick
authors.initials: K
authors.lastname: Semple
authors.affiliation: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Lynette S
authors.initials: LS
authors.lastname: Chea
authors.affiliation: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: William R
authors.initials: WR
authors.lastname: Proctor
authors.affiliation: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Bourdi
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.affiliation: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Xiangbin
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Ryan
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dagur
authors.affiliation: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Julia D
authors.initials: JD
authors.lastname: Berkson
authors.affiliation: Exploratory Clinical & Translational Research, Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Reilly
authors.affiliation: Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Lance R
authors.initials: LR
authors.lastname: Pohl
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D039481:CD11b Antigen / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006221:Halothane / Q000633:toxicity*; D006505:Hepatitis / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D011897:Random Allocation
chemical_list: D039481:CD11b Antigen; D009569:Nitric Oxide; D000410:Alanine Transaminase; D006221:Halothane