Role of innate and adaptive immunity during drug-induced liver injury

Abstract

Drug-induced liver injury (DILI) is a major human health concern and is the most frequent cause of FDA boxed warnings and the removal of drugs from the market. Idiosyncratic DILI (IDILI) is highly variable in its time to onset and no one clear hypothesis exists to explain the mechanism. The general belief is most cases of IDILI involve some immune mediated component; however no animal models can recapitulate human IDILI. Despite numerous drugs that have IDILI potential, the most common cause of DILI is acetaminophen (APAP) overdose. APAP in animal models and in patients is a dose-dependent hepatotoxicant resulting in severe centrilobular necrosis and a robust inflammatory response. In this review we will compare the existing hypotheses for potential causes of IDILI and discuss the potential roles of immune involvement in DILI. Additionally we will focus on what we have learned from the mechanisms of APAP toxicity (protein adduction, mitochondrial dysfunction, oxidant stress, DNA damage, release of damage associated molecular patterns (DAMPs)) and useful interventions to alleviate APAP-toxicity (reduced protein binding, scavenging of reactive oxygen, induction of autophagy). Mechanistically APAP-induced liver injury appears to be fundamentally different from IDILI, however, there are potential critical events shared between APAP-induced liver injury and IDILI. The strategies and methods currently being used to study APAP-induced liver injury are described in this review. This improved insight into mechanisms of APAP-induced injury with initiation, propagation and inflammation may also help to better understand IDILI.