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One report of this phenomenon was the increased incidence of hypersensitivity reactions observed in patients receiving concurrent immune checkpoint inhibitors (ICIs) and sulfasalazine (SLZ). Thus, the aim of this study was to characterize the T cells involved in the pathogenesis of such reactions, and recapitulate the effects of inhibitory checkpoint blockade on de-novo priming responses to compounds within in vitro platforms. A regulatory competent human dendritic cell\/T-cell coculture assay was used to model the effects of ICIs on de novo nitroso sulfamethoxazole- and sulfapyridine (SP) (the sulfonamide component of SLZ) hydroxylamine-specific priming responses. The role of T cells in the pathogenesis of the observed reactions was explored in 3 patients through phenotypic characterization of SP\/sulfapyridine hydroxylamine (SPHA)-responsive T-cell clones (TCC), and assessment of cross-reactivity and pathways of T-cell activation. Augmentation of the frequency of responding drug-specific T cells and intensity of the T-cell response was observed with PD-1\/PD-L1 blockade. Monoclonal populations of SP- and SPHA-responsive T cells were isolated from all 3 patients. A core secretory effector molecule profile (IFN-\u03b3, IL-13, granzyme B, and perforin) was identified for SP and SPHA-responsive TCC, which proceeded through Pi and hapten mechanisms, respectively. Data presented herein provides evidence that drug-responsive T cells are effectors of hypersensitivity reactions observed in oncology patients administered ICIs and SLZ. Perturbation of drug-specific T-cell priming is a plausible explanation for clinical observations of how an increased incidence of these adverse events is occurring.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab144","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T16:10:11Z","timestamp":1637683811000},"page":"58-69","source":"Crossref","is-referenced-by-count":41,"title":["Checkpoint Inhibition Reduces the Threshold for Drug-Specific T-Cell Priming and Increases the Incidence of Sulfasalazine Hypersensitivity"],"prefix":"10.1093","volume":"186","author":[{"given":"Sean","family":"Hammond","sequence":"first","affiliation":[{"name":"D epartment of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK"},{"name":"ApconiX, Alderley Edge SK10 4TG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Olsson-Brown","sequence":"additional","affiliation":[{"name":"D epartment of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Grice","sequence":"additional","affiliation":[{"name":"D epartment of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Gibson","sequence":"additional","affiliation":[{"name":"Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, WA 6150, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Gardner","sequence":"additional","affiliation":[{"name":"D epartment of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Luis","family":"Castrej\u00f3n-Flores","sequence":"additional","affiliation":[{"name":"Instituto Polit\u00e9cnico Nacional, Unidad Profesional Interdisciplinaria de Biotecnolog\u00eda, Mexico City 07340, M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Jolly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4631-549X","authenticated-orcid":false,"given":"Benjamin Alexis","family":"Fisher","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK"},{"name":"National Institute of Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK"},{"name":"Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Steven","sequence":"additional","affiliation":[{"name":"Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK"},{"name":"Cancer Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Betts","sequence":"additional","affiliation":[{"name":"Pathology Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7534-7266","authenticated-orcid":false,"given":"Munir","family":"Pirmohamed","sequence":"additional","affiliation":[{"name":"D epartment of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Meng","sequence":"additional","affiliation":[{"name":"D epartment of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4107-7832","authenticated-orcid":false,"given":"Dean John","family":"Naisbitt","sequence":"additional","affiliation":[{"name":"D epartment of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"2022022809423027900_kfab144-B1","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.1021\/acs.chemrestox.7b00263","article-title":"Dapsone and nitroso dapsone activation of naive T-cells from healthy donors","volume":"30","author":"Alzahrani","year":"2017","journal-title":"Chem. 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