Characterization of Drug-Specific CD4+T-Cells Reveals Possible Roles of HLA Class II in the Pathogenesis of Carbamazepine Hypersensitivity Reactions

Jaruthamsophon, Kanoot, Thomson, Paul J ORCID: 0000-0001-5431-0459, Hammond, Sean, Zhang, Eunice, Alfirevic, Ana ORCID: 0000-0002-2801-9817, Sukasem, Chonlaphat, Naisbitt, Dean J and Pirmohamed, Munir ORCID: 0000-0002-7534-7266
(2023) Characterization of Drug-Specific CD4+T-Cells Reveals Possible Roles of HLA Class II in the Pathogenesis of Carbamazepine Hypersensitivity Reactions. CHEMICAL RESEARCH IN TOXICOLOGY, 36 (5). pp. 757-768.

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Carbamazepine (CBZ) is an aromatic anticonvulsant known to cause drug hypersensitivity reactions, which range in severity from relatively mild maculopapular exanthema to potentially fatal Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN). These reactions are known to be associated with human leukocyte antigen (HLA) class I alleles, and CBZ interacts preferentially with the related HLA proteins to activate CD8<sup>+</sup> T-cells. This study aimed to evaluate the contribution of HLA class II in the effector mechanism(s) of CBZ hypersensitivity. CBZ-specific T-cells clones were generated from two healthy donors and two hypersensitive patients with high-risk HLA class I markers. Phenotype, function, HLA allele restriction, response pathways, and cross-reactivity of CBZ-specific T-cells were assessed using flow cytometry, proliferation analysis, enzyme-linked immunosorbent spot, and enzyme-linked immunosorbent assay. The association between HLA class II allele restriction and CBZ hypersensitivity was reviewed using Allele Frequency Net Database. Forty-four polyclonal CD4<sup>+</sup> CBZ-specific T-cell clones were generated and found to be restricted to HLA-DR, particularly <i>HLA-DRB1*07:01</i>. This CD4<sup>+</sup>-mediated response proceeded through a direct pharmacological interaction between CBZ and HLA-DR molecules. Similar to the CD8<sup>+</sup> response, CBZ-stimulated CD4<sup>+</sup> clones secreted granulysin, a key mediator of SJS-TEN. Our database review revealed an association between <i>HLA-DRB1*07:01</i> and CBZ-induced SJS-TEN. These findings implicate HLA class II antigen presentation as an additional pathogenic factor for CBZ hypersensitivity reactions. Both HLA class II molecules and drug-responsive CD4<sup>+</sup> T-cells should be evaluated further to gain better insights into the pathogenesis of drug hypersensitivity reactions.

Item Type: Article
Uncontrolled Keywords: CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Humans, Stevens-Johnson Syndrome, Drug Hypersensitivity, Carbamazepine, Anticonvulsants, HLA-B Antigens, HLA Antigens, HLA-DRB1 Chains
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 19 May 2023 07:58
Last Modified: 26 May 2023 04:30
DOI: 10.1021/acs.chemrestox.2c00414
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