Drug‐induced allergic hepatitis develops in mice when myeloid‐derived suppressor cells are depleted prior to halothane treatment

Abstract

Clinical evidence suggests that many cases of serious idiosyncratic drug-induced liver injury are mediated by the adaptive immune system in response to hepatic drug-protein adducts, also referred to as "drug-induced allergic hepatitis"; but detailed mechanistic proof has remained elusive due to the lack of animal models. We have hypothesized that drug-induced allergic hepatitis is as rare in animals as it is in humans due at least in part to the tolerogenic nature of the liver. We provide evidence that immune tolerance can be overcome in a murine model of halothane-induced liver injury initiated by trifluoroacetylated protein adducts of halothane formed in the liver. Twenty-four hours after female Balb/cJ mice were initially treated with halothane, perivenous necrosis and an infiltration of CD11b Gr-1 high cells were depleted from the liver with Gr-1 antibody treatment, enhanced liver injury was observed at 9 days after halothane rechallenge. Toxicity was associated with increased serum levels of interleukin-4 and immunoglobulins G1 and E directed against hepatic trifluoroacetylated protein adducts, as well as increased hepatic infiltration of eosinophils and CD41 T cells, all features of an allergic reaction. When hepatic CD41 T cells were depleted 5 days after halothane rechallenge, trifluoroacetylated protein adduct-specific serum immunoglobulin and hepatotoxicity were reduced. Conclusion: Our data provide a rational approach for developing animal models of drug-induced allergic hepatitis mediated by the adaptive immune system and suggest that impaired liver tolerance may predispose patients to this disease. (HEPATOLOGY 2015;62:546-557)

Mechanisms of adaptation and progression in idiosyncratic drug induced liver injury, clinical implications

“…The unpredictable and experimentally irreproducible nature of idiosyncratic hepatotoxicity has made it particularly difficult to study in animal models. Recently two independent groups have used the concept of defective adaptation to develop mouse models for IDILI . Metushi et al .…”

“…The unpredictable and experimentally irreproducible nature of idiosyncratic hepatotoxicity has made it particularly difficult to study in animal models. Recently two independent groups have used the concept of defective adaptation to develop mouse models for IDILI (41,42). Metushi et al examined toxicity from amodiaquine in female mice defective in two genes implicated in immune-tolerance: Casitas B-lineage Lymphoma (Cbl-b1), an E3 ubiquitin ligase; and programmed cell death 1 (PD-1), a negative regulator of T cell activation (41).…”

Effects of immunization and checkpoint inhibition on amodiaquine-induced liver injury

“…As mentioned, we had previously found that immunization with AQ-modified hepatic proteins paradoxically protected animals from liver injury when subsequently challenged with AQ, and this was accompanied by a large increase in cells associated with immune tolerance. Multiple reports have also shown that inhibition of immune tolerance leads to animal models of IDILI with characteristics similar to IDILI that occurs in humans (Chakraborty et al 2015;Metushi et al 2015). However, patients who develop IDILI are unlikely to have this severe impairment of immune tolerance, and therefore these models are more likely useful to understand the steps leading to IDILI, but not who will develop IDILI.…”

Xenobiotic and Endobiotic Mediated Interactions Between the Cytochrome P450 System and the Inflammatory Response in the Liver

“…It should be noted that dendritic cell depleted mice had higher levels of neutrophils in their non-parenchymal fraction after dendritic cell depletion; however, this was excluded a cause of increased injury (Connolly et al, 2011). Myeloid derived suppressor cells (MDSC) may also be involved in some forms of drug-induced immune mediated liver injury as a recent study indicates that MDSCs may link innate and adaptive immunity and play a key role in immune tolerance to molecules such as halothane (Chakraborty et al, 2015). Further work is required in these cell populations before a full understanding of how they function and how they affect interactions between P450s and the innate immune system.…”

“…Although there is only limited evidence for the pathogenic role for these auto-antibodies in a majority of IDILI type injuries, their presence is an independent predictor of outcome in patients with numerous drug-mediated liver injuries (Sutti et al, 2014). A recent study using a novel model of drug (halothane)-induced allergic hepatitis suggests that auto-antibodies against protein adducts may be critical to liver injury in IDILI (Chakraborty et al, 2015). Further research in this area is needed, as both removal of pharmaceuticals from the market due to previously undescribed DILI, and clinical liver injury, can be attributed to IDILI and our current lack of understanding of this topic.…”