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Review
. 2010 Jun;115(2):307-21.
doi: 10.1093/toxsci/kfq009. Epub 2010 Jan 13.

Mechanisms of immune-mediated liver injury

Affiliations
Review

Mechanisms of immune-mediated liver injury

David H Adams et al. Toxicol Sci. 2010 Jun.

Abstract

Hepatic inflammation is a common finding during a variety of liver diseases including drug-induced liver toxicity. The inflammatory phenotype can be attributed to the innate immune response generated by Kupffer cells, monocytes, neutrophils, and lymphocytes. The adaptive immune system is also influenced by the innate immune response leading to liver damage. This review summarizes recent advances in specific mechanisms of immune-mediated hepatotoxicity and its application to drug-induced liver injury. Basic mechanisms of activation of lymphocytes, macrophages, and neutrophils and their unique mechanisms of recruitment into the liver vasculature are discussed. In particular, the role of adhesion molecules and various inflammatory mediators in this process are explored. In addition, the authors describe mechanisms of liver cell damage by these inflammatory cells and critically evaluate the functional significance of each cell type for predictive and idiosyncratic drug-induced liver injury. It is expected that continued advances in our understanding of immune mechanisms of liver injury will lead to an earlier detection of the hepatotoxic potential of drugs under development and to an earlier identification of susceptible individuals at risk for predictive and idiosyncratic drug toxicities.

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Figures

FIG. 1.
FIG. 1.
Lymphocyte adhesion mechanisms in liver sinusoids. Lymphocytes bind to HSECs in a modified version of the classic adhesion cascade model. Selectins, which are involved in capture in other vascular beds, play a minimal role in the liver, and other molecules including VAP-1 may be involved in this stage. Chemokines presented by the endothelial glycocalyx then trigger integrin-mediated adhesion to ICAM-1 and VCAM-1, and transmigration into tissue is driven by multiple poorly understood molecular mechanisms that involve VAP-1, chemokines, and integrins. The HSECs exist in close proximity to stellate cells and hepatocytes.
FIG. 2.
FIG. 2.
Drug-induced classic adaptive immune responses and autoimmune responses. Depending on which helper T cells happen to have the highest affinity, the dominant immune response induced by a drug-modified protein may be a classic adaptive immune response against the drug or an autoimmune response against the protein portion of the modified protein. Th17 cells appear to play a major role in autoimmune responses; however, any immune response is likely to involve a combination of multiple types of T cells and B cells as well as innate immune cells.
FIG. 3.
FIG. 3.
Dual function of sterile inflammation. Drugs or chemicals cause cell injury and necrosis, which results in the release of cellular contents including DNA, RNA, and proteins (HMGB1, HSPs). These DAMPs can cause complement activation or bind to toll-like receptors on neutrophils and macrophages where they trigger cytokine and chemokine formation. These proinflammatory mediators can activate neutrophils and monocytes in blood and recruit them into the liver vasculature. After extravasation into the parenchyma and adherence to target cells, neutrophils generate potent reactive oxygen species, which trigger cell death (cytotoxicity). On the other hand, both macrophages and neutrophils can phagocytose cell debris and digest it (clean-up mission). Whether these phagocytes cause additional tissue damage or mainly remove cell debris depends on the individual drug. If the drug itself effectively causes cell death, a cytotoxic effect of neutrophils is less likely. However, if the drug induces significant stress in many cells but is able to kill only a few, the recruited neutrophils may aggravate the injury by attacking and killing some of the stressed cells. C5a, activated complement factor C5a; HMGB1, high mobility group box-1 protein; HOCl, hypochlorous acid; HSPs, heat shock proteins; TLRs, toll-like receptors.
FIG. 4.
FIG. 4.
DILI: future strategies to incorporate in vivo models and biomarkers to address immune cell mechanisms.

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