PMID- 33912179 OWN - NLM STAT- MEDLINE DCOM- 20210927 LR - 20210927 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - 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. PG - 653710 LID - 10.3389/fimmu.2021.653710 [doi] LID - 653710 AB - 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. IFNgamma) 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 alphabetaTCR, 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. CI - Copyright (c) 2021 Mifsud, Illing, Lai, Fettke, Hensen, Huang, Rossjohn, Vivian, Kwan and Purcell. FAU - Mifsud, Nicole A AU - Mifsud NA AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. FAU - Illing, Patricia T AU - Illing PT AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. FAU - Lai, Jeffrey W AU - Lai JW AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. FAU - Fettke, Heidi AU - Fettke H AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. FAU - Hensen, Luca AU - Hensen L AD - Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia. FAU - Huang, Ziyi AU - Huang Z AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. FAU - Rossjohn, Jamie AU - Rossjohn J AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. AD - Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia. AD - Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom. FAU - Vivian, Julian P AU - Vivian JP AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. AD - Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia. FAU - Kwan, Patrick AU - Kwan P AD - Department of Neuroscience, Central Clinical School, Alfred Hospital, Monash University, Melbourne, VIC, Australia. AD - Departments of Medicine and Neurology, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia. AD - Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, Hong Kong. FAU - Purcell, Anthony W AU - Purcell AW AD - Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. LA - eng PT - Journal Article PT - Observational Study PT - Research Support, Non-U.S. Gov't DEP - 20210412 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Anticonvulsants) RN - 0 (HLA-B*15:02 antigen) RN - 0 (HLA-B15 Antigen) RN - 0 (Peptides) RN - 0 (Receptors, Antigen, T-Cell) RN - 33CM23913M (Carbamazepine) SB - IM MH - Anticonvulsants/*adverse effects MH - CD8-Positive T-Lymphocytes/drug effects/*immunology/metabolism MH - Carbamazepine/*adverse effects MH - Case-Control Studies MH - Cell Line, Tumor MH - Clonal Selection, Antigen-Mediated/*drug effects/genetics MH - Female MH - HLA-B15 Antigen/analysis/metabolism MH - Healthy Volunteers MH - Humans MH - Immunologic Memory/drug effects MH - Male MH - Peptides/analysis/metabolism MH - Primary Cell Culture MH - Proteomics MH - Receptors, Antigen, T-Cell/genetics/metabolism MH - Stevens-Johnson Syndrome/blood/*immunology PMC - PMC8071863 OTO - NOTNLM OT - SJS OT - Stevens-Johnson syndrome OT - T cell receptor OT - T cells OT - carbamazepine OT - drug hypersensitivity OT - immunopeptidomics COIS- 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. EDAT- 2021/04/30 06:00 MHDA- 2021/09/28 06:00 PMCR- 2021/01/01 CRDT- 2021/04/29 06:26 PHST- 2021/01/15 00:00 [received] PHST- 2021/03/22 00:00 [accepted] PHST- 2021/04/29 06:26 [entrez] PHST- 2021/04/30 06:00 [pubmed] PHST- 2021/09/28 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.653710 [doi] PST - epublish SO - Front Immunol. 2021 Apr 12;12:653710. doi: 10.3389/fimmu.2021.653710. eCollection 2021.