Thomson, Paul 
ORCID: 0000-0001-5431-0459, Fragkas, Nik, Kafu, Laila M, Aithal, Guruprasad P, Lucena, M Isabel, Terracciano, Luigi, Meng, Xiaoli, Pirmohamed, Munir, Brees, Dominique, Kullak‐Ublick, Gerd A et al (show 4 more authors)
(2024)
Patients with <scp>naproxen‐induced</scp> liver injury display T‐cell memory responses toward an oxidative (S)‐<scp>O‐Desmethyl</scp> Naproxen metabolite but not the acyl glucuronide.
Allergy, 79 (1).
pp. 200-214.
Abstract
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Exposure to nonsteroidal anti‐inflammatory drugs (NSAIDs) such as ibuprofen (IBU) and naproxen (NAP) is associated with idiosyncratic drug‐induced liver injury (DILI). Carboxylate bioactivation into reactive metabolites (e.g., acyl glucuronides, AG) and resulting T‐cell activation is hypothesized as causal for this adverse event. However, conclusive evidence supporting this is lacking.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In this work, we identify CD4<jats:sup>+</jats:sup> and CD8<jats:sup>+</jats:sup> T‐cell hepatic infiltration in a biopsy from an IBU DILI patient. Lymphocyte transformation test and IFN‐γ ELIspot, conducted on peripheral blood mononuclear cells (PBMCs) of patients with NAP‐DILI, were used to explore drug‐specific T‐cell activation. T‐cell clones (TCC) were generated and tested for drug specificity, phenotype/function, and pathways of T‐cell activation. Cells were exposed to NAP, its oxidative metabolite 6‐O‐desmethyl NAP (DM‐NAP), its AG or synthesized NAP‐AG human‐serum albumin adducts (NAP‐AG adduct).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>CD4<jats:sup>+</jats:sup> and CD8<jats:sup>+</jats:sup> T‐cells from patients expressing a range of different Vβ receptors were stimulated to proliferate and secrete IFN‐γ and IL‐22 when exposed to DM‐NAP, but <jats:italic>not</jats:italic> NAP, NAP‐AG or the NAP‐AG adduct. Activation of the CD4<jats:sup>+</jats:sup> TCC was HLA‐DQ‐restricted and dependent on antigen presenting cells (APC); most TCC were activated with DM‐NAP‐pulsed APC, while fixation of APC blocked the T‐cell response. Cross‐reactivity was not observed with structurally‐related drugs.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our results confirm hepatic T‐cell infiltrations in NSAID‐induced DILI, and show a T‐cell memory response toward DM‐NAP indicating an immune‐mediated basis for the adverse event. Whilst bioactivation at the carboxylate group is widely hypothesized to be pathogenic for NSAID associated DILI, we found no evidence of this with NAP.</jats:p></jats:sec>
| Item Type: | Article |
|---|---|
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 22 Aug 2023 10:31 |
| Last Modified: | 08 Jan 2024 02:58 |
| DOI: | 10.1111/all.15830 |
| Open Access URL: | https://doi.org/10.1111/all.15830 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3172290 |
Dimensions
Dimensions
