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
Authors | 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. |
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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. |
Keywords | allopurinol; drug hypersensitivity reaction; oxypurinol; T-cell receptor |
Year | 01 Jan 2023 |
Journal | Allergy |
Journal citation | 78 (11), pp. 2980-2993 |
Publisher | Wiley-Blackwell Publishing Ltd. (UK) |
ISSN | 0105-4538 |
Digital Object Identifier (DOI) | https://doi.org/10.1111/all.15814 |
Web address (URL) | https://onlinelibrary.wiley.com/doi/10.1111/all.15814 |
Open access | Published as ‘gold’ (paid) open access |
Research or scholarly | Research |
Page range | 2980-2993 |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 10 Nov 2023 |
Publication process dates | |
Accepted | 10 Jun 2023 |
Deposited | 12 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. | |
Place of publication | United Kingdom |
https://acuresearchbank.acu.edu.au/item/9046y/the-allopurinol-metabolite-oxypurinol-drives-oligoclonal-expansions-of-drug-reactive-t-cells-in-resolved-hypersensitivity-cases-and-drug-na-ve-healthy-donors
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Publisher's version
OA_Vivian_2023_The_allopurinol_metabolite_oxypurinol_drives_oligoclonal.pdf | |
License: CC BY-NC-ND 4.0 | |
File access level: Open |
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