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

Author

Listed:
  • 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
    National Yang-Ming University)

  • Chuang-Wei Wang

    (Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou
    Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Immunology Consortium, Chang Gung Memorial Hospital)

  • 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
    Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Immunology Consortium, Chang Gung Memorial Hospital
    Chang Gung University)

  • Elizabeth Jane Phillips

    (Vanderbilt University
    Murdoch University)

  • Simon Alexander Mallal

    (Vanderbilt University
    Murdoch 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
    Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Immunology Consortium, Chang Gung Memorial Hospital
    Chang Gung University
    Xiamen Chang Gung Hospital)

  • Shuen-Iu Hung

    (Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Immunology Consortium, Chang Gung Memorial Hospital
    National Yang-Ming University)

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.

Suggested Citation

  • 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 , 2019. "Identification of drug-specific public TCR driving severe cutaneous adverse reactions," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11396-2
    DOI: 10.1038/s41467-019-11396-2
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