A novel model of drug hapten-induced hepatitis with increased mast cells in the BALB/c mouse

Dolores B Njoku, Monica V. Talor, Delisa Fairweather, Sylvia Frisancho-Kiss, Oludare A. Odumade, Noel R. Rose

Research output: Contribution to journalArticle

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-α, IL-1β, 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.

Original languageEnglish (US)
Pages (from-to)87-100
Number of pages14
JournalExperimental and Molecular Pathology
Volume78
Issue number2
DOIs
StatePublished - Apr 2005

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Chemical and Drug Induced Liver Injury
Haptens
Mast Cells
Hepatitis
Anesthetics
Liver
Interleukin-6
Pharmaceutical Preparations
Cytokines
Immunization
Proteins
Kupffer Cells
Interleukin-1
Infiltration
Interleukin-10
Autoantibodies
Immunoglobulin G
Antibodies
Autoimmune Hepatitis
S100 Proteins

Keywords

  • Cytokines
  • Drug hapten
  • Drug-induced hepatitis

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Molecular Biology
  • Pathology and Forensic Medicine

Cite this

A novel model of drug hapten-induced hepatitis with increased mast cells in the BALB/c mouse. / Njoku, Dolores B; Talor, Monica V.; Fairweather, Delisa; Frisancho-Kiss, Sylvia; Odumade, Oludare A.; Rose, Noel R.

In: Experimental and Molecular Pathology, Vol. 78, No. 2, 04.2005, p. 87-100.

Research output: Contribution to journalArticle

Njoku, Dolores B ; Talor, Monica V. ; Fairweather, Delisa ; Frisancho-Kiss, Sylvia ; Odumade, Oludare A. ; Rose, Noel R. / A novel model of drug hapten-induced hepatitis with increased mast cells in the BALB/c mouse. In: Experimental and Molecular Pathology. 2005 ; Vol. 78, No. 2. pp. 87-100.
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