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



Kim, Seung-Hyun, Saide, Katy, Farrell, John ORCID: 0000-0002-8726-5997, Faulkner, Lee, Tailor, Arun ORCID: 0000-0002-9698-3480, Ogese, Monday ORCID: 0000-0002-1873-4032, Daly, Ann K, Pirmohamed, Munir ORCID: 0000-0002-7534-7266, Park, B Kevin ORCID: 0000-0001-8384-824X and Naisbitt, Dean J
(2015) Characterization of amoxicillin‐ and clavulanic acid‐specific T cells in patients with amoxicillin‐clavulanate–induced liver injury. Hepatology, 62 (3). 887 - 899.

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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. (Hepatology 2015;62:887‐899)

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 04 Jul 2016 10:11
Last Modified: 27 Nov 2021 15:39
DOI: 10.1002/hep.27912
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3002006