Projects per year
Abstract
Antiseizure medications (ASMs) are frequently implicated in T cell-mediated drug hypersensitivity reactions and cause skin tropic pathologies that range in severity from mild rashes to life-threatening systemic syndromes. During the acute stages of the more severe manifestations of these reactions, drug responsive proinflammatory CD8+ T cells display classical features of Th1 cytokine production (e.g. IFNγ) and cytolysis (e.g. granzyme B, perforin). These T cells may be found locally at the site of pathology (e.g. blister cells/fluid), as well as systemically (e.g. blood, organs). What is less understood are the long-lived immunological effects of the memory T cell pool following T cell-mediated drug hypersensitivity reactions. In this study, we examine the ASM carbamazepine (CBZ) and the CBZ-reactive memory T cell pool in patients who have a history of either Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) from 3-to-20 years following their initial adverse reaction. We show that in vitro drug restimulation of CBZ-reactive CD8+ T cells results in a proinflammatory profile and produces a mainly focused, yet private, T cell receptor (TCR) usage amongst human leukocyte antigen (HLA)-B*15:02-positive SJS or TEN patients. Additionally, we show that expression of these CBZ-reactive TCRs in a reporter cell line, lacking endogenous αβTCR, recapitulates the features of TCR activation reported for ASM-treated T cell lines/clones, providing a useful tool for further functional validations. Finally, we conduct a comprehensive evaluation of the HLA-B*15:02 immunopeptidome following ASM (or a metabolite) treatment of a HLA-B*15:02-positive B-lymphoblastoid cell line (C1R.B*15:02) and minor perturbation of the peptide repertoire. Collectively, this study shows that the CBZ-reactive T cells characterized require both the drug and HLA-B*15:02 for activation and that reactivation of memory T cells from blood results in a focused private TCR profile in patients with resolved disease.
Original language | English |
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Article number | 653710 |
Number of pages | 20 |
Journal | Frontiers in Immunology |
Volume | 12 |
DOIs | |
Publication status | Published - 12 Apr 2021 |
Keywords
- carbamazepine
- drug hypersensitivity
- immunopeptidomics
- SJS
- Stevens-Johnson syndrome
- T cell receptor
- T cells
Projects
- 5 Finished
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Genomics of antiepileptic drug-induced Stevens Johnson syndrome
Kwan, P., Petrovski, S. & Sham, P.
1/01/18 → 31/12/19
Project: Research
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Understanding the complexity of antigen presentation
National Health and Medical Research Council (NHMRC) (Australia)
1/01/18 → 31/12/22
Project: Research
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Precision medicine for epilepsy and beyond: from discovery to implementation and evaluation
1/01/18 → 31/12/22
Project: Research