Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome - 30/11/11
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Abstract |
Background |
Stevens-Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), are life-threatening drug hypersensitivities with robust immune responses to drugs. Despite the strong HLA predisposition to drug hypersensitivities, such as HLA-B1502 to carbamazepine (CBZ)–induced SJS/TEN, it remains unknown whether particular T-cell receptors (TCRs) participate in recognition of small drug/peptide–HLA complexes.
Objective |
Using the strong HLA predisposition in patients with CBZ-induced SJS/TEN as a model, we aimed to study the use of TCR repertoire in patients with drug hypersensitivity.
Method |
We enrolled patients with CBZ-SJS/TEN, tolerant control subjects, and healthy subjects who had no history of CBZ exposure. We isolated PBMCs from the subjects, cultured CBZ-specific T cells, and globally investigated the expression level and third complementarity-determining region length distribution of the TCR profile. We further assessed the pathogenic role of the disease-specific clonotype using real-time PCR–based tests and functional analysis.
Results |
On drug stimulation, CBZ-specific CD8+ T cells were expanded in vitro and activated to release granulysin. Notably, VB-11-ISGSY was identified as the most predominant clonotype and shared among different subjects. This clonotype was present in 16 (84%) of 19 patients with SJS/TEN, absent in all 17 tolerant patients, and present at a low frequency in healthy subjects (4/29 [14%]). CBZ-specific cytotoxicity could be primed in vitro in the PBMCs of healthy subjects who are carriers of HLA-B1502 and VB-11-ISGSY; this cytotoxicity could be blocked by an anti–TCR-VB-11 antibody. Furthermore, a single T-cell clone expressing VA-22-FISGTY/VB-11-ISGSY showed significant cytotoxicity against HLA-B
1502–positive antigen-presenting cells and CBZ.
Conclusion |
This study establishes the key role of the TCR in the pathogenic mechanism of SJS/TEN, explains why some HLA-B1502 carriers are tolerant to CBZ, and provides a biomarker profile for drug hypersensitivity.
Key words : Drug hypersensitivity, T-cell receptor, HLA, third complementarity-determining region, Stevens-Johnson syndrome, toxic epidermal necrolysis
Abbreviations used : B-LCL, CA, CB, CBZ, CDR3, 51Cr, CTL, GBP, HSS, OXC, SJS, TCR, TEN, VA, VB
Plan
Supported by grants from the National Science Council, Taiwan (NSC95-2314-B-010-096, 95-2314-B-182A-048, 95-3112-B-001-010, 95-3112-B-001-011, 96-2320-B-010-021-MY2, 96-2628-B-182A-065-MY2, NSC 97-2745-B-010-001, 98-2320-B-010-002-MY3, 98-2314-B-182A-027-MY3); the Taiwanese Ministry of Education (Aim for the Top University Plan, National Yang-Ming University); the Academia Sinica Thematic Research Program (AS-99-TP-B12); and Chang-Gung Memorial Hospital. |
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Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. |
Vol 128 - N° 6
P. 1266 - décembre 2011 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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