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Human Leukocyte Antigen (HLA)-B(star)57:01-Restricted Activation of Drug-Specific T Cells Provides the Immunological Basis for Flucloxacillin-Induced Liver Injury

Lookup NU author(s): Professor Ann Daly

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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 CD41 and CD81 T cells from patients with liver injury and show that naive CD45RA1CD81 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-gamma), 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 CD81 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 beta-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. (HEPATOLOGY 2013; 57:727-739)


Publication metadata

Author(s): Monshi MM, Faulkner L, Gibson A, Jenkins RE, Farrell J, Earnshaw CJ, Alfirevic A, Cederbrant K, Daly AK, French N, Pirmohamed M, Park BK, Naisbitt DJ

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 2013

Volume: 57

Issue: 2

Pages: 727-739

Print publication date: 01/02/2013

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/hep.26077

DOI: 10.1002/hep.26077


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