Tolerogenic role of Kupffer cells in immune-mediated adverse drug reactions

Immune-mediated adverse drug reactions (IADR) account for approximately 6-10% of all adverse drug reactions. Although IADR are often referred to as rare (afflicting 1/100 to 1/100,000 patients), their unpredictable and serious nature makes them a significant economic burden and safety concern to the health care community and the pharmaceutical industry. Current studies suggest that IADR are caused by immunogenic drug-protein adducts; however, it remains unclear why only a small percentage of patients are susceptible to developing these reactions. We hypothesized that most individuals may be resistant to IADR because they develop immunological tolerance to drug-protein adducts in the liver, an organ with tolerogenic properties. We tested this hypothesis using a murine model of T-cell-mediated reaction against a hapten, 2,4-dinitrochlorobenzene (DNCB). We showed that pre-treatment of mice with a protein adduct of DNCB led to its accumulation in Kupffer cells (KC) of the liver and induced tolerance to subsequent DNCB sensitization. KC depletion and adoptive transfer experiments further supported that KC may act as a primary inducer of immunological tolerance against protein adducts of haptens or drugs. Functional activities of KC, which are regulated by genetic and/or environmental factors, may play an important role in determining individual susceptibility to IADR.