1. Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury.
- Author
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Monshi MM, Faulkner L, Gibson A, Jenkins RE, Farrell J, Earnshaw CJ, Alfirevic A, Cederbrant K, Daly AK, French N, Pirmohamed M, Park BK, and Naisbitt DJ
- Subjects
- Aged, Aged, 80 and over, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cell Movement drug effects, Chemical and Drug Induced Liver Injury immunology, Clone Cells immunology, Female, Floxacillin metabolism, HLA-B Antigens immunology, Humans, Interferon-gamma metabolism, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear immunology, Lymphocyte Activation drug effects, Lysine metabolism, Male, Middle Aged, Receptors, CCR biosynthesis, Receptors, CCR4 biosynthesis, Serum Albumin metabolism, Chemical and Drug Induced Liver Injury etiology, Floxacillin adverse effects, HLA-B Antigens physiology, Lymphocyte Activation immunology
- Abstract
Unlabelled: 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., Conclusion: This work defines the immune basis for flucloxacillin-induced liver injury and links the genetic association to the iatrogenic disease., (Copyright © 2012 American Association for the Study of Liver Diseases.)
- Published
- 2013
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