Immunological mechanisms in drug-induced liver injury

Immune-mediated injury plays a primary or secondary role in many forms of drug-induced liver injury (DILI) (1,2). This mechanism of DILI is suggested clinically by the presence of features of systemic immune activation such as concomitant fever, rash, atypical lymphocytes, and/or eosinophilia. When drug rechallenge occurs, immune-mediated mechanisms of DILI are confirmed by the development of an accelerated onset of equally or more severe liver injury indicating the presence of immunological memory, the signature of an adaptive immune response (1,3). In many such cases, hepatic drug metabolism has been found to produce reactive metabolites that haptenate or alkylate self proteins which in turn elicit adaptive immune responses and associated liver injury in genetically susceptible individuals (2,4-6). More recently, it has been recognized that drugs that directly injure hepatocytes may also trigger innate immune responses apparently directed at damaged hepatocytes (2,7,8).