1. Carbamazepine Induces Focused T Cell Responses in Resolved Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Cases But Does Not Perturb the Immunopeptidome for T Cell Recognition.
- Author
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Mifsud NA, Illing PT, Lai JW, Fettke H, Hensen L, Huang Z, Rossjohn J, Vivian JP, Kwan P, and Purcell AW
- Subjects
- CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes metabolism, Case-Control Studies, Cell Line, Tumor, Clonal Selection, Antigen-Mediated genetics, Female, HLA-B15 Antigen analysis, HLA-B15 Antigen metabolism, Healthy Volunteers, Humans, Immunologic Memory drug effects, Male, Peptides analysis, Peptides metabolism, Primary Cell Culture, Proteomics, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, Stevens-Johnson Syndrome blood, Anticonvulsants adverse effects, CD8-Positive T-Lymphocytes immunology, Carbamazepine adverse effects, Clonal Selection, Antigen-Mediated drug effects, Stevens-Johnson Syndrome immunology
- 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mifsud, Illing, Lai, Fettke, Hensen, Huang, Rossjohn, Vivian, Kwan and Purcell.)- Published
- 2021
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