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Hepatology. 2015 Sep;62(3):887-99. doi: 10.1002/hep.27912. Epub 2015 Jul 23.

Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury.

Author information

1
MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
2
Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
3
Institute of Cellular Medicine, Newcastle University, Medical School, Newcastle upon Tyne, United Kingdom.
4
The Wolfson Center for Personalized Medicine, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.

Abstract

Drug-induced liver injury (DILI) frequently has a delayed onset with several human leukocyte antigen (HLA) genotypes affecting susceptibility, indicating a potential role for the adaptive immune system in the disease. The aim of this study was to investigate whether drug-responsive T lymphocytes are detectable in patients who developed DILI with the combination, antimicrobial amoxicillin-clavulanate. Lymphocytes from 6 of 7 patients were found to proliferate and/or secrete interferon-gamma (IFN-γ) when cultured with amoxicillin and/or clavulanic acid. Amoxicillin (n = 105) and clavulanic acid (n = 16) responsive CD4(+) and CD8(+) T-cell clones expressing CCR, chemokine (C-C motif) receptor 4, CCR9, and chemokine (C-X-C motif) receptor 3 were generated from patients with and without HLA risk alleles; no cross-reactivity was observed between the two drug antigens. Amoxicillin clones were found to secrete a heterogeneous panel of mediators, including IFN-γ, interleukin-22 and cytolytic molecules. In contrast, cytokine secretion by the clavulanic acid clones was more restricted. CD4(+) and CD8(+) clones were major histocompatability complex class II and I restricted, respectively, with the drug antigen being presented to CD4(+) clones in the context of HLA-DR molecules. Several pieces of evidence indicate that the clones were activated by a hapten mechanism: First, professional antigen-presenting cells (APCs) were required for optimal activation; second, pulsing APCs for 4-16 hours activated the clones; and third, inhibition of processing abrogated the proliferative response and cytokine release.

CONCLUSION:

Both amoxicillin- and clavulanic acid-specific T cells participate in the liver injury that develops in certain patients exposed to amoxicillin-clavulanate.

PMID:
25998949
DOI:
10.1002/hep.27912
[Indexed for MEDLINE]

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