dc.contributor.author | Phillips, Elizabeth Jane | |
dc.contributor.author | Mallal, Simon Alexander | |
dc.date.accessioned | 2020-07-10T15:51:39Z | |
dc.date.available | 2020-07-10T15:51:39Z | |
dc.date.issued | 2019-08-08 | |
dc.identifier.citation | Pan, R., Chu, M., Wang, C. et al. Identification of drug-specific public TCR driving severe cutaneous adverse reactions. Nat Commun 10, 3569 (2019). https://doi.org/10.1038/s41467-019-11396-2 | en_US |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | http://hdl.handle.net/1803/10179 | |
dc.description | Only Vanderbilt University affiliated authors are listed on VUIR. For a full list of authors, access the version of record at https://www.nature.com/articles/s41467-019-11396-2#Ack1 | en_US |
dc.description.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 alpha beta TCR 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 alpha beta TCR has binding affinity for carbamazepine and its structural analogs, thereby mediating the immune response. Adoptive transfer of T cell expressing this public alpha beta TCR 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. | en_US |
dc.description.sponsorship | We thank the support of members of the Whole-Genome Research Core Laboratory of Human Diseases, and the Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Taiwan. This work was supported in part by grants from the Ministry of Science and Technology, Taiwan (MOST 102-2314-B-010-014-MY3, 103-2321-B-182-001, 104-2314-B-182A-148-MY3, 104-2325-B-182A-006, 104-2320-B-010-036-MY3, 105-2628-B-010-007-MY3, 106-2314-B-182A-037-MY3), and Chang Gung Memorial Hospital (CLRPG2E0051 similar to 3, CORPG3F0041 similar to 2, OMRPG3E0041, CMRPG1F0111 similar to 2, CORPG3F0061 similar to 2, CIRPG3I0041). Most funds for the European RegiSCAR group came from a research grant from the European Commission (QLRT-2002-01738). Maja Mockenhaupt received the Else Kroner Memorial Stipendium for support of clinical research through the Else Kroner-Fresenius-Foundation. Methodological costs were partly funded by the Deutsche Forschungsgemeinschaft (FOR 534). E.P. and S.M. received funding from National Institutes of Health (1P50GM115305-01, R21AI139021 and R34AI136815) and the National Health and Medical Research Foundation of Australia. W.T. received funding from the Faculty of Medicine, Khon Kaen University, Thailand (IN61233 and IN61301) and National Science and Technology Development Agency, Thailand. | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | Nature Communications | en_US |
dc.rights | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. | |
dc.source.uri | https://www.nature.com/articles/s41467-019-11396-2#Ack1 | |
dc.subject | STEVENS-JOHNSON-SYNDROME | en_US |
dc.subject | TOXIC EPIDERMAL NECROLYSIS | en_US |
dc.subject | INFILTRATING T-CELLS | en_US |
dc.subject | HYPERSENSITIVITY REACTIONS | en_US |
dc.subject | IMMUNOLOGICAL BASIS | en_US |
dc.subject | SEQUENCING REVEALS | en_US |
dc.subject | HLA | en_US |
dc.subject | HLA-B-ASTERISK-5701 | en_US |
dc.subject | ASSOCIATION | en_US |
dc.subject | ACTIVATION | en_US |
dc.title | Identification of drug-specific public TCR driving severe cutaneous adverse reactions | en_US |
dc.type | Article | en_US |
dc.identifier.doi | 10.1038/s41467-019-11396-2 | |