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

Ren-You Pan, Mu-Tzu Chu, Chuang-Wei Wang, Yun-Shien Lee, Francois Lemonnier, Aaron W. Michels, Ryan Schutte, David A. Ostrov, Chun-Bing Chen, Elizabeth Jane Phillips, Simon Alexander Mallal, Maja Mockenhaupt, Teresa Bellón, Wichittra Tassaneeyakul, Katie D. White, Jean-Claude Roujeau, Wen-Hung Chung () and Shuen-Iu Hung ()
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Ren-You Pan: Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou
Mu-Tzu Chu: Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Immunology Consortium, Chang Gung Memorial Hospital
Chuang-Wei Wang: Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou
Yun-Shien Lee: Ming Chuan University
Francois Lemonnier: INSERM U1016, Institut Cochin, Equipe Immunologie du Diabète, Hôpital Saint-Vincent-de-Paul
Aaron W. Michels: University of Colorado Denver
Ryan Schutte: University of Florida College of Medicine
David A. Ostrov: University of Florida College of Medicine
Chun-Bing Chen: Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou
Elizabeth Jane Phillips: Vanderbilt University
Simon Alexander Mallal: Vanderbilt University
Maja Mockenhaupt: Medical Center and Medical Faculty, University of Freiburg
Teresa Bellón: Research Unit, Hospital Universitario La Paz-Idi PAZ
Wichittra Tassaneeyakul: Khon Kaen University
Katie D. White: Vanderbilt University
Jean-Claude Roujeau: Université Paris-Est Créteil (UPEC)
Wen-Hung Chung: Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou
Shuen-Iu Hung: Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Immunology Consortium, Chang Gung Memorial Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11396-2

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