Identification of drug-specific public TCR driving severe cutaneous adverse reactions.

Pan RY, Chu MT, Wang CW, Lee YS, Lemonnier F, Michels AW, Schutte R, Ostrov DA, Chen CB, Phillips EJ, Mallal SA, Mockenhaupt M, Bellón T, Tassaneeyakul W, White KD, Roujeau JC, Chung WH, Hung SI
Nat Commun. 2019 10 (1): 3569

PMID: 31395875 · PMCID: PMC6687717 · DOI:10.1038/s41467-019-11396-2

Drug hypersensitivity such as severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), could be life-threatening. Here, we enroll SCAR patients to investigate the T cell receptor (TCR) repertoire by next-generation sequencing. A public αβTCR is identified from the cytotoxic T lymphocytes of patients with carbamazepine-SJS/TEN, with its expression showing drug/phenotype-specificity and an bias for HLA-B*15:02. This public αβTCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public αβTCR to HLA-B*15:02 transgenic mice receiving oral administration of carbamazepine induces multi-organ injuries and symptoms mimicking SCAR, including hair loss, erythema, increase of inflammatory lymphocytes in the skin and blood, and liver and kidney dysfunction. Our results not only demonstrate an essential role of TCR in the immune synapse mediating SCAR, but also implicate potential clinical applications and development of therapeutics.

MeSH Terms (18)

Adoptive Transfer Adult Aged Animals Carbamazepine Disease Models, Animal Female HLA-B15 Antigen Humans Male Mice, Transgenic Middle Aged Receptor-CD3 Complex, Antigen, T-Cell Receptors, Antigen, T-Cell, alpha-beta Severity of Illness Index Skin Stevens-Johnson Syndrome T-Lymphocytes, Cytotoxic

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