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.