Immune Mechanisms in Drug-Induced Liver Injury

Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

Drug-induced liver injury is a serious clinical problem and a challenge for drug development. Although intracellular events including formation of reactive metabolites and oxidant stress are well-established causes of cell injury, immune mechanisms of liver injury are coming more into focus recently. Acute liver injury as observed after acetaminophen overdose leads to release of damage-associated molecular patterns (DAMPs), which triggers formation of cytokines and chemokines through activation of toll like receptors and other pattern recognition receptors causing the activation of innate immune cells including neutrophils, Kupffer cells, and monocytes. The general purpose of this innate immune response is to recruit phagocytes into the areas of necrosis to remove necrotic cells and prepare for regeneration of the lost tissue. However, an excessive innate immune response may cause additional cell death and exaggerate the original injury. The factors that trigger a proinjury versus a proregenerative innate immune response during drug-induced liver injury remain to be investigated. On the other hand, a prolonged subclinical stress caused by therapeutic doses of certain drugs can trigger activation of T and B lymphocytes and an adaptive immune-mediated liver injury in susceptible individuals. Although specific HLA alleles have been identified as risk factors for drug hepatotoxicity, there is still limited understanding of the mechanisms of adaptive immune cell activation, the development of immune tolerance and the mechanisms of cell death in patients. The chapter summarizes the current knowledge on innate and adaptive immune-mediated liver injury mechanisms in drug hepatotoxicity.

Key words

Drug-induced liver injury Acetaminophen Innate immunity Neutrophils Monocytes Adaptive immunity T cells IgG Flucloxacillin 

Notes

Acknowledgments

The authors’ laboratory was supported in part by the National Institutes of Health grants R01 DK070195 (to H.J.), and by grants P20 GM103549 and P30 GM118247 (to H.J.) from the National Institute of General Medical Sciences of the National Institutes of Health and the UK Medical Research Council (Centre for Drug Safety Science grant G0700654) (to D.J.N.).

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityUSA
  2. 2.Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety ScienceUniversity of LiverpoolLiverpoolUK

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