title: Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury.
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.
  
  
  CONCLUSIONS
  Both amoxicillin- and clavulanic acid-specific T cells participate in the liver injury that develops in certain patients exposed to amoxicillin-clavulanate.
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.|Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: Katy
authors.initials: K
authors.lastname: Saide
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Farrell
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: Lee
authors.initials: L
authors.lastname: Faulkner
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: Arun
authors.initials: A
authors.lastname: Tailor
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: Monday
authors.initials: M
authors.lastname: Ogese
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Medical School, Newcastle upon Tyne, United Kingdom.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.|The Wolfson Center for Personalized Medicine, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.affiliation: MRC Center for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Naisbitt
mesh_terms: D000368:Aged; D000658:Amoxicillin / Q000009:adverse effects* / Q000276:immunology; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000009:adverse effects; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology*; D019818:Clavulanic Acid / Q000009:adverse effects* / Q000276:immunology; D002999:Clone Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D012494:Sampling Studies
chemical_list: D019818:Clavulanic Acid; D019980:Amoxicillin-Potassium Clavulanate Combination; D000658:Amoxicillin