T Cells Infiltrate the Liver and Kill Hepatocytes in HLA-B∗57:01-Associated Floxacillin-Induced Liver Injury

Wuillemin, Natascha; Terracciano, Luigi; Beltraminelli, Helmut; Schlapbach, Christoph; Fontana, Stefano; Krähenbühl, Stephan; Pichler, Werner J.; Yerly, Daniel

doi:10.1016/j.ajpath.2014.02.018

Cited by 63 publications

(58 citation statements)

References 36 publications

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“…Mechanistically, there are two large groups, namely immunological and non-immunological (also called metabolic) idiosyncratic adverse drug reactions [13]. As shown for flucloxacillin [14,15], abacavir [16] or lumiracoxib [17], certain human leukocyte antigen (HLA) constellations, e.g., the presence of HLA-B*5701, are known susceptibility factors for immunological idiosyncratic adverse drug reactions. Regarding metabolic idiosyncratic adverse drug reactions, susceptibility factors include, for instance, underlying metabolic diseases, mainly causing disturbances of mitochondrial metabolism.…”

Section: Definition and Principle Mechanisms Of Hepatotoxicitymentioning

confidence: 99%

Hepatotoxicity of New Oral Anticoagulants (NOACs)

2015

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Case reports and analyses of clinical studies and of pharmacovigilance data suggest that new oral anticoagulants (NOACs) are associated with a small risk for hepatotoxicity. The objective of this publication is to summarize the current data about this subject, with a special emphasis on pharmacovigilance data in the World Health Organization (WHO) Global Individual Case Safety Reports (ICSR) database and on potential mechanisms of hepatotoxicity. For that, all available case reports as well as published analyses of clinical studies were obtained with a detailed search in PubMed. In addition, pharmacovigilance data from VigiBase(®), the WHO Global ICRS database, were extracted and analyzed. The data show that liver injury associated with NOACs was reported in clinical studies and in pharmacovigilance databases. Several case reports described potentially life-threatening hepatotoxicity in patients treated with rivaroxaban or dabigatran. For rivaroxaban, most affected patients were symptomatic and liver injury was most often hepatocellular or mixed. The frequency was between 0.1 and 1 % in clinical studies and was by trend lower than for comparators (mostly enoxaparin or warfarin). Comparing the pharmacovigilance reports for the individual NOACs, more hepatic adverse events were reported for rivaroxaban than for dabigatran or apixaban. With the exception of edoxaban, for which only few reports are available, patients with acute liver failure have been reported for every NOAC, but most patients had concomitant drugs or diseases. So far, there are no clear mechanisms explaining the hepatotoxicity of these drugs. We conclude that hepatotoxicity appears to be associated with all NOACs currently on the market. Hepatotoxicity associated with NOACs is idiosyncratic; it appears at therapeutic doses, is rare and the mechanism is not related to the pharmacological action of these drugs. Prescribers should inform patients about possible symptoms of hepatotoxicity and stop these drugs in patients presenting with severe liver injury.

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Section: Definition and Principle Mechanisms Of Hepatotoxicitymentioning

confidence: 99%

Hepatotoxicity of New Oral Anticoagulants (NOACs)

2015

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“…However, there may be other factors contributing to an immune-mediated drug reaction. The evidence that supports an immunological aetiology for iDILI includes the delayed onset where symptoms appear only several weeks after the administration of the drug, 56,57 an increase in susceptibility to iDILI where immune activation has already occurred due to viral infection, 18 the presence of T-cells in liver biopsies from patients with iDILI 58,59 and the isolation of drug-specific T-cells in patients with iDILI. 10 The liver is an immune-privileged organ so that the mechanisms that maintain the tolerogenic microenvironment must be overcome for immune activation to occur.…”

Section: Immune Mechanisms Of Liver Injurymentioning

confidence: 99%

“…79 Most recently, CD8þ T-cells were found in a liver biopsy, and flucloxacillin-specific T-cells, generated in vitro from normal volunteers carrying HLA B*57:01, were shown to kill liver cell lines transfected with HLA B*57:01. 59 Exposure of experimental animals to flucloxacillin may also result in the activation of naive CD8þ T-cells. Drug treatment ex vivo resulted in the secretion of interferon g and granzyme B and the induction of hepatocyte apoptosis.…”

Section: Flucloxacillinmentioning

confidence: 99%

The chemical, genetic and immunological basis of idiosyncratic drug–induced liver injury

et al. 2015

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Idiosyncratic drug reactions can be extremely severe and are not accounted for by the regular pharmacology of a drug. Thus, the mechanism of idiosyncratic drug–induced liver injury (iDILI), a phenomenon that occurs with many drugs including β-lactams, anti-tuberculosis drugs and non-steroidal anti-inflammatories, has been difficult to determine and remains a pressing issue for patients and drug companies. Evidence has shown that iDILI is multifactorial and multifaceted, which suggests that multiple cellular mechanisms may be involved. However, a common initiating event has been proposed to be the formation of reactive drug metabolites and covalently bound adducts. Although the fate of these metabolites are unclear, recent evidence has shown a possible link between iDILI and the adaptive immune system. This review highlights the role of reactive metabolites, the recent genetic innovations which have provided molecular targets for iDILI, and the current literature which suggests an immunological basis for iDILI.

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“…This finding suggested promiscuous T-cell responses to flucloxacillin and flucloxacillin-hapten may co-exist and predominant T-cell response may be affected by individual immunological factors. Furthermore, the infiltration of cytotoxic CD8 + T lymphocytes is found in the liver biopsies of a patient with flucloxacillin-induced liver injury, 73 where cytotoxic T-cells could kill hepatocytes in a perforin/granzyme B-dependent manner. Moreover, bystander killing caused by FasL could lead to exacerbation of liver injury caused by flucloxacillin.…”

Section: Hla-b*5701mentioning

confidence: 99%

“…Moreover, bystander killing caused by FasL could lead to exacerbation of liver injury caused by flucloxacillin. 73 An alternative hypothesis has been suggested as a mechanism behind interactions between drug and HLA molecules in abacavir-induced hypersensitivity. [74][75][76] Abacavir can bind inside the peptide-binding groove of HLA-B*5701, changing the shape, finally leading to the alteration in the repertoire of peptide that can bind HLA-B*5701.…”

Section: Hla-b*5701mentioning

confidence: 99%

Update on Advances in Research on Idiosyncratic Drug-Induced Liver Injury

Kim

Naisbitt

2016

Allergy Asthma Immunol Res

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Drug-induced liver injury (DILI) is a major concern for public health, as well as for drug development in the pharmaceutical industry, since it can cause liver failure and lead to drug withdrawal from the market and black box warnings. Thus, it is important to identify biomarkers for early prediction to increase our understanding of mechanisms underlying DILI that will ultimately aid in the exploration of novel therapeutic strategies to prevent or manage DILI. DILI can be subdivided into 'intrinsic' and 'idiosyncratic' categories, although the validity of this classification remains controversial. Idiosyncratic DILI occurs in a minority of susceptible individuals with a prolonged latency, while intrinsic DILI results from drug-induced direct hepatotoxicity over the course of a few days. The rare occurrence of idiosyncratic DILI requires multicenter collaborative investigations and phenotype standardization. Recent progress in research on idiosyncratic DILI is based on key developments in 3 areas: (1) newly developed highthroughput genotyping across the whole genome allowing for the identification of genetic susceptibility markers, (2) new mechanistic concepts on the pathogenesis of DILI revealing a key role of drug-responsive T lymphocytes in the immunological response, and (3) broad multidisciplinary approaches using different platform "-omics" technologies that have identified novel biomarkers for the prediction of DILI. An association of a specific human leukocyte antigen (HLA) allele with DILI has been reported for several drugs. HLA-restricted T-cell immune responses have also been investigated using lymphocytes and T-cell clones isolated from patients. A microRNA, miR-122, has been discovered as a promising biomarker for the early prediction of DILI. In this review, we summarize recent advances in research on idiosyncratic DILI with an understanding of the key role of adaptive immune systems.

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T Cells Infiltrate the Liver and Kill Hepatocytes in HLA-B∗57:01-Associated Floxacillin-Induced Liver Injury

Cited by 63 publications

References 36 publications

Hepatotoxicity of New Oral Anticoagulants (NOACs)

Hepatotoxicity of New Oral Anticoagulants (NOACs)

The chemical, genetic and immunological basis of idiosyncratic drug–induced liver injury

Update on Advances in Research on Idiosyncratic Drug-Induced Liver Injury

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