The allopurinol metabolite, oxypurinol, drives oligoclonal expansions of drug-reactive T cells in resolved hypersensitivity cases and drug-naïve healthy donors

Journal article


Mifsud, Nicole A., Illing, Patricia T., Ho, Rebecca, Tuomisto, Johanna E., Fettke, Heidi, Mullan, Kerry A., McCluskey, James, Rossjohn, Jamie, Vivian, Julian Philip, Reantragoon, Rangsima and Purcell, Anthony W.. (2023). The allopurinol metabolite, oxypurinol, drives oligoclonal expansions of drug-reactive T cells in resolved hypersensitivity cases and drug-naïve healthy donors. Allergy. 78(11), pp. 2980-2993. https://doi.org/10.1111/all.15814
AuthorsMifsud, Nicole A., Illing, Patricia T., Ho, Rebecca, Tuomisto, Johanna E., Fettke, Heidi, Mullan, Kerry A., McCluskey, James, Rossjohn, Jamie, Vivian, Julian Philip, Reantragoon, Rangsima and Purcell, Anthony W.
Abstract

Allopurinol (ALP) is a successful drug used in the treatment of gout. However, this drug has been implicated in hypersensitivity reactions that can cause severe to life-threatening reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Individuals who carry the human leukocyte antigen (HLA)-B*58:01 allotype are at higher risk of experiencing a hypersensitivity reaction (odds ratios ranging from 5.62 to 580.3 for mild to severe reactions, respectively). In addition to the parent drug, the metabolite oxypurinol (OXP) is implicated in triggering T cell-mediated immunopathology via a labile interaction with HLA-B*58:01. To date, there has been limited information regarding the T-cell receptor (TCR) repertoire usage of reactive T cells in patients with ALP-induced SJS or TEN and, in particular, there are no reports examining paired αβTCRs. Here, using in vitro drug-treated PBMCs isolated from both resolved ALP-induced SJS/TEN cases and drug-naïve healthy donors, we show that OXP is the driver of CD8+ T cell-mediated responses and that drug-exposed memory T cells can exhibit a proinflammatory immunophenotype similar to T cells described during active disease. Furthermore, this response supported the pharmacological interaction with immune receptors (p-i) concept by showcasing (i) the labile metabolite interaction with peptide/HLA complexes, (ii) immunogenic complex formation at the cell surface, and (iii) lack of requirement for antigen processing to elicit drug-induced T cell responsiveness. Examination of paired OXP-induced αβTCR repertoires highlighted an oligoclonal and private clonotypic profile in both resolved ALP-induced SJS/TEN cases and drug-naïve healthy donors.

Keywordsallopurinol; drug hypersensitivity reaction; oxypurinol; T-cell receptor
Year01 Jan 2023
JournalAllergy
Journal citation78 (11), pp. 2980-2993
PublisherWiley-Blackwell Publishing Ltd. (UK)
ISSN0105-4538
Digital Object Identifier (DOI)https://doi.org/10.1111/all.15814
Web address (URL)https://onlinelibrary.wiley.com/doi/10.1111/all.15814
Open accessPublished as ‘gold’ (paid) open access
Research or scholarlyResearch
Page range2980-2993
Publisher's version
License
File Access Level
Open
Output statusPublished
Publication dates
Online10 Nov 2023
Publication process dates
Accepted10 Jun 2023
Deposited12 Mar 2024
Additional information

© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
http://creativecommons.org/licenses/by-nc-nd/4.0/

Place of publicationUnited Kingdom
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