Human Leukocyte Antigen (HLA)-B*57:01-Restricted Activation ... : Hepatology (original) (raw)

Autoimmune, Cholestatic and Biliary Disease

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

Monshi, Manal M.1,2; Faulkner, Lee1; Gibson, Andrew1; Jenkins, Rosalind E.1; Farrell, John1; Earnshaw, Caroline J.1; Alfirevic, Ana3; Cederbrant, Karin4; Daly, Ann K.5; French, Neil1; Pirmohamed, Munir3; Park, Kevin B.1; Naisbitt, Dean J.10

1_MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Liverpool, UK_

2_Faculty of Medicine, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia_

3_Wolfson Centre for Personalised Medicine, Department of Pharmacology, University of Liverpool, Liverpool, UK_

4_Molecular Toxicology, Global Safety Assessment, AstraZeneca R&D, Södertälje, Sweden_

5_Institute of Cellular Medicine, Newcastle University Medical School, Newcastle Upon Tyne, UK_

Address reprint requests to: Dean J. Naisbitt, MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool L69 3GE, UK

E-mail:[email protected]

Received 10 July 2012; Accepted 4 September 2012

fax: 0044 151 7945540

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.

Conclusion:

This work defines the immune basis for flucloxacillin-induced liver injury and links the genetic association to the iatrogenic disease.