TY - JOUR
T1 - Identification of drug-specific public TCR driving severe cutaneous adverse reactions
AU - Pan, Ren You
AU - Chu, Mu Tzu
AU - Wang, Chuang Wei
AU - Lee, Yun Shien
AU - Lemonnier, Francois
AU - Michels, Aaron W.
AU - Schutte, Ryan
AU - Ostrov, David A.
AU - Chen, Chun Bing
AU - Phillips, Elizabeth Jane
AU - Mallal, Simon Alexander
AU - Mockenhaupt, Maja
AU - Bellón, Teresa
AU - Tassaneeyakul, Wichittra
AU - White, Katie D.
AU - Roujeau, Jean Claude
AU - Chung, Wen Hung
AU - Hung, Shuen Iu
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85070418088
U2 - 10.1038/s41467-019-11396-2
DO - 10.1038/s41467-019-11396-2
M3 - 文章
C2 - 31395875
AN - SCOPUS:85070418088
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3569
ER -
