Immunological mechanisms of drug-induced liver injury.

Immune-mediated drug-induced liver injury (DILI) occurs at a relatively low rate, but the outcome can often be serious and sometimes fatal. As a result, it represents a major problem in drug development and safety. The key to predicting and preventing immune-mediated DILI is to understand the underlying mechanisms. Currently, the most prevalent working model is the hapten hypothesis, which proposes that drugs, or more often their reactive metabolites, bind to endogenous proteins to form immunogenic conjugates that cause T-cell- or antibody-mediated pathological reactions. Another working model incorporates the hypothesis that most people are tolerant to immune-mediated DILI, and that these reactions only occur when the tolerance mechanism is impaired. Understanding the molecular and cellular elements in these models can help identify risk factors, and ultimately facilitate the development of prediction and prevention strategies.