Lookup NU author(s): Professor Ann Daly
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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-) 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-, 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. (Hepatology 2015;62:887-899)
Author(s): Kim SH, Saide K, Farrell J, Faulkner L, Tailor A, Ogese M, Daly AK, Pirmohamed M, Park BK, Naisbitt DJ
Publication type: Article
Publication status: Published
Print publication date: 01/09/2015
Online publication date: 23/07/2015
Acceptance date: 11/05/2015
ISSN (print): 0270-9139
ISSN (electronic): 1527-3350
Publisher: John Wiley & Sons, Inc.
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