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Carboxylate bioactivation into reactive metabolites (e.g., acyl glucuronides, AG) and resulting T\u2010cell 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\u2010cell hepatic infiltration in a biopsy from an IBU DILI patient. Lymphocyte transformation test and IFN\u2010\u03b3 ELIspot, conducted on peripheral blood mononuclear cells (PBMCs) of patients with NAP\u2010DILI, were used to explore drug\u2010specific T\u2010cell activation. T\u2010cell clones (TCC) were generated and tested for drug specificity, phenotype\/function, and pathways of T\u2010cell activation. Cells were exposed to NAP, its oxidative metabolite 6\u2010O\u2010desmethyl NAP (DM\u2010NAP), its AG or synthesized NAP\u2010AG human\u2010serum albumin adducts (NAP\u2010AG 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\u2010cells from patients expressing a range of different V\u03b2 receptors were stimulated to proliferate and secrete IFN\u2010\u03b3 and IL\u201022 when exposed to DM\u2010NAP, but <jats:italic>not<\/jats:italic> NAP, NAP\u2010AG or the NAP\u2010AG adduct. Activation of the CD4<jats:sup>+<\/jats:sup> TCC was HLA\u2010DQ\u2010restricted and dependent on antigen presenting cells (APC); most TCC were activated with DM\u2010NAP\u2010pulsed APC, while fixation of APC blocked the T\u2010cell response. Cross\u2010reactivity was not observed with structurally\u2010related drugs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results confirm hepatic T\u2010cell infiltrations in NSAID\u2010induced DILI, and show a T\u2010cell memory response toward DM\u2010NAP indicating an immune\u2010mediated 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>","DOI":"10.1111\/all.15830","type":"journal-article","created":{"date-parts":[[2023,7,29]],"date-time":"2023-07-29T09:00:40Z","timestamp":1690621240000},"page":"200-214","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Patients with <scp>naproxen\u2010induced<\/scp> liver injury display T\u2010cell memory responses toward an oxidative (S)\u2010<scp>O\u2010desmethyl<\/scp> naproxen metabolite but not the acyl glucuronide"],"prefix":"10.1111","volume":"79","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5431-0459","authenticated-orcid":false,"given":"Paul","family":"Thomson","sequence":"first","affiliation":[{"name":"Molecular&amp; Clinical Pharmacology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nik","family":"Fragkas","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laila M.","family":"Kafu","sequence":"additional","affiliation":[{"name":"Molecular&amp; Clinical Pharmacology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guruprasad P.","family":"Aithal","sequence":"additional","affiliation":[{"name":"NIHR Nottingham Biomedical Research Centre and Nottingham Digestive Diseases Centre, Translational Medical Sciences, West Block, Queen's Medical Centre University of Nottingham  Nottingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Isabel","family":"Lucena","sequence":"additional","affiliation":[{"name":"Unidad de Gesti\u00f3n Cl\u00ednica de Aparato Digestivo y Servicio de Farmacolog\u00eda Cl\u00ednica, Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga\u2010IBIMA, Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga, CIBERehd  Malaga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Terracciano","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Hospital Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Meng","sequence":"additional","affiliation":[{"name":"Molecular&amp; Clinical Pharmacology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munir","family":"Pirmohamed","sequence":"additional","affiliation":[{"name":"Molecular&amp; Clinical Pharmacology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Brees","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd A.","family":"Kullak\u2010Ublick","sequence":"additional","affiliation":[{"name":"University Hospital Zurich University of Zurich  Zurich Switzerland"},{"name":"Novartis Global Drug Development  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Odermatt","sequence":"additional","affiliation":[{"name":"Division of Molecular &amp; Systems Toxicology, Department of Pharmaceutical Sciences University of Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hammond","sequence":"additional","affiliation":[{"name":"Division of Molecular &amp; Systems Toxicology, Department of Pharmaceutical Sciences University of Basel  Basel Switzerland"},{"name":"Oncology Safety, Clinical Pharmacology and Safety Sciences R&amp;D  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kamm\u00fcller","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4107-7832","authenticated-orcid":false,"given":"Dean J.","family":"Naisbitt","sequence":"additional","affiliation":[{"name":"Molecular&amp; Clinical Pharmacology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1185\/03007998409109557"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.162982"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.TM118.006295"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/key444"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2017.07.037"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.15645"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2011.574613"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1542-3565(04)00777-3"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2010.214"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2007.06.004"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20205"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1056-8719(99)00014-3"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02353639"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/js9802704"},{"issue":"10","key":"e_1_2_11_16_1","first-page":"1050","article-title":"Stereoselective irreversible binding of ketoprofen glucuronides to albumin. 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