title: A novel model of drug hapten-induced hepatitis with increased mast cells in the BALB/c mouse.
abstract: Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated volatile anesthetics is mediated by autoimmune responses. No murine model to study mechanisms of anesthetic-induced or any other form of drug-induced idiosyncratic hepatitis exists. Anesthetics are believed to trigger hepatitis by covalently linking a trifluoroacetyl (TFA) chloride hapten to hepatic proteins, forming haptenated self-proteins. To test this hypothesis, we developed a hapten-induced model of hepatitis by immunization with syngeneic S100 liver proteins covalently coupled to TFA (TFA-S100). We found that TFA-S100 induced hepatitis was more severe than disease induced by S100 plus adjuvants or by the adjuvant alone and was characterized by neutrophil, mast cell, and eosinophil infiltration. TFA-specific IgG1 antibodies directly correlated with hepatitis, whereas S100 autoantibodies did not. TNF-alpha, IL-1beta, and IL-6 released from splenocytes collected 2 weeks after TFA-S100 inoculation were increased resembling the elevated serum cytokines reported in patients with autoimmune hepatitis (AIH). Three weeks after inoculation, the peak of hepatitis, we noted decreased numbers of Kupffer cells and lower levels of IL-6 and IL-10 in the liver, cytokines produced by Kupffer cells. This is the first report, to our knowledge, of a hapten-induced model of hepatitis with immune and autoimmune features.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Blalock 906A, 600 North Wolfe Street, Baltimore, MD 21287, USA. dnjoku@jhmi.edu
authors.forename: Dolores B
authors.initials: DB
authors.lastname: Njoku
authors.forename: Monica V
authors.initials: MV
authors.lastname: Talor
authors.forename: Delisa
authors.initials: D
authors.lastname: Fairweather
authors.forename: Sylvia
authors.initials: S
authors.lastname: Frisancho-Kiss
authors.forename: Oludare A
authors.initials: OA
authors.lastname: Odumade
authors.forename: Noel R
authors.initials: NR
authors.lastname: Rose
mesh_terms: D018685:Anesthetics, Inhalation / Q000009:adverse effects / Q000276:immunology; D000818:Animals; D001323:Autoantibodies; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D004195:Disease Models, Animal; D005463:Fluoroacetates; D006241:Haptens / Q000276:immunology*; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008407:Mast Cells / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009418:S100 Proteins / Q000276:immunology*; D014269:Trifluoroacetic Acid / Q000737:chemistry / Q000276:immunology
chemical_list: D018685:Anesthetics, Inhalation; D001323:Autoantibodies; D016207:Cytokines; D005463:Fluoroacetates; D006241:Haptens; D009418:S100 Proteins; C500395:trifluoroacetyl chloride; D014269:Trifluoroacetic Acid