title: Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury.
abstract: The role of the adaptive immune system in adverse drug reactions that target the liver has not been defined. For flucloxacillin, a delay in the reaction onset and identification of human leukocyte antigen (HLA)-B*57:01 as a susceptibility factor are indicative of an immune pathogenesis. Thus, we characterize flucloxacillin-responsive CD4+ and CD8+ T cells from patients with liver injury and show that naive CD45RA+CD8+ T cells from volunteers expressing HLA-B*57:01 are activated with flucloxacillin when dendritic cells present the drug antigen. T-cell clones expressing CCR4 and CCR9 migrated toward CCL17 and CCL 25, and secreted interferon-gamma (IFN-γ), T helper (Th)2 cytokines, perforin, granzyme B, and FasL following drug stimulation. Flucloxacillin bound covalently to selective lysine residues on albumin in a time-dependent manner and the level of binding correlated directly with the stimulation of clones. Activation of CD8+ clones with flucloxacillin was processing-dependent and restricted by HLA-B*57:01 and the closely related HLA-B*58:01. Clones displayed additional reactivity against β-lactam antibiotics including oxacillin, cloxacillin, and dicloxacillin, but not abacavir or nitroso sulfamethoxazole.
  
  
  CONCLUSIONS
  This work defines the immune basis for flucloxacillin-induced liver injury and links the genetic association to the iatrogenic disease.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Manal M
authors.initials: MM
authors.lastname: Monshi
authors.forename: Lee
authors.initials: L
authors.lastname: Faulkner
authors.forename: Andrew
authors.initials: A
authors.lastname: Gibson
authors.forename: Rosalind E
authors.initials: RE
authors.lastname: Jenkins
authors.forename: John
authors.initials: J
authors.lastname: Farrell
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Earnshaw
authors.forename: Ana
authors.initials: A
authors.lastname: Alfirevic
authors.forename: Karin
authors.initials: K
authors.lastname: Cederbrant
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.forename: Neil
authors.initials: N
authors.lastname: French
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Naisbitt
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology; D002999:Clone Cells / Q000276:immunology; D005260:Female; D005436:Floxacillin / Q000009:adverse effects* / Q000378:metabolism; D015235:HLA-B Antigens / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008239:Lysine / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D054388:Receptors, CCR / Q000096:biosynthesis; D054398:Receptors, CCR4 / Q000096:biosynthesis; D012709:Serum Albumin / Q000378:metabolism
chemical_list: C119309:CC chemokine receptor 9; C515354:CCR4 protein, human; D015235:HLA-B Antigens; C103707:HLA-B57 antigen; C041533:HLA-B58 antigen; D054388:Receptors, CCR; D054398:Receptors, CCR4; D012709:Serum Albumin; D005436:Floxacillin; D007371:Interferon-gamma; D008239:Lysine