The Immunological Mechanisms and Immune-Based Biomarkers of Drug-Induced Liver Injury

Abstract

Drug-induced liver injury (DILI) has become one of the major challenges of drug safety all over the word. So far, about 1,100 commonly used drugs including the medications used regularly, herbal and/or dietary supplements, have been reported to induce liver injury. Moreover, DILI is the main cause of the interruption of new drugs development and drugs withdrawn from the pharmaceutical market. Acute DILI may evolve into chronic DILI or even worse, commonly lead to life-threatening acute liver failure in Western countries. It is generally considered to have a close relationship to genetic factors, environmental risk factors, and host immunity, through the drug itself or its metabolites, leading to a series of cellular events, such as haptenization and immune response activation. Despite many researches on DILI, the specific biomarkers about it are not applicable to clinical diagnosis, which still relies on the exclusion of other causes of liver disease in clinical practice as before. Additionally, circumstantial evidence has suggested that DILI is mediated by the immune system. Here, we review the underlying mechanisms of the immune response to DILI and provide guidance for the future development of biomarkers for the early detection, prediction, and diagnosis of DILI.

Keywords: biomarker; drug-induced liver injury; immune; immune response; mechanism.

FIGURE 1

The role of innate immunity and adaptive immunity in DILI. Drug or their reactive metabolites lead to cell stress, damage, or death, which release some molecules that recruit and activate innate immune cells prompting the release of pro-inflammatory cytokines. These mediators stimulate adaptive immune cells, ultimately resulting in the activation of T cells into effector cells and B cells into plasma cell–released antibodies. During the activation of innate and adaptive immunity, the host immune tolerance–related immune cells or cytokine may exert immunosuppressive effects. However, if the balance is broken, this will further aggravate the inflammatory response in the liver.

FIGURE 2

Mechanisms of immunity in DILI. DILI is a disorder by drugs-induced liver damage, including pharmacological therapies, traditional medicines, and HDS. If the number of reactive metabolites produced exceeds the detoxification capacity, activated innate immune system–related cells, e.g., NKT, NK, dendritic cells, Kupffer cells, neutrophils and eosinophils, and the released various cytokines, form the cytokine storm. Furthermore, inducing adaptive immunity, activating T and B cells, producing effector T cells and antibodies, then liver damage all occur. However, Tregs may exert an immunosuppressive effect on APCs, effector T cells, and mast cells by the following mechanisms: coinhibitory receptors binding to cognate molecules on dendritic cells, secretion of inhibitory cytokines, e.g., IL-10 and TGF-β, metabolic disruption by depriving IL-2 binding and increasing adenosine binding to effector T cells, and contact-dependent cytolysis by granzyme B secretion. Abbreviations: NKT, natural killer T cells; NK, natural killer cells; Treg, regulatory T cells; MDSC, myeloid-derived suppressor cells; DAMPs, danger-associated molecular patterns; IFN-γ, interferon gamma; IL-6, interleukin 6; TNF-α, tumor necrosis factor-α; IL-10 interleukin 10; TGF-β, transforming growth factor-β1; IL-17, interleukin 17; Ab, antibody; ROS, reactive oxygen species; iNOS, inducible nitric oxide synthase.