PMID- 37074725 OWN - NLM STAT- MEDLINE DCOM- 20230516 LR - 20230525 IS - 1520-5010 (Electronic) IS - 0893-228X (Print) IS - 0893-228X (Linking) VI - 36 IP - 5 DP - 2023 May 15 TI - Characterization of Drug-Specific CD4(+) T-Cells Reveals Possible Roles of HLA Class II in the Pathogenesis of Carbamazepine Hypersensitivity Reactions. PG - 757-768 LID - 10.1021/acs.chemrestox.2c00414 [doi] AB - 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(+) 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(+) CBZ-specific T-cell clones were generated and found to be restricted to HLA-DR, particularly HLA-DRB1*07:01. This CD4(+)-mediated response proceeded through a direct pharmacological interaction between CBZ and HLA-DR molecules. Similar to the CD8(+) response, CBZ-stimulated CD4(+) clones secreted granulysin, a key mediator of SJS-TEN. Our database review revealed an association between HLA-DRB1*07:01 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(+) T-cells should be evaluated further to gain better insights into the pathogenesis of drug hypersensitivity reactions. FAU - Jaruthamsophon, Kanoot AU - Jaruthamsophon K AUID- ORCID: 0000-0003-1563-0024 AD - Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K. AD - Department of Pathology, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand. FAU - Thomson, Paul J AU - Thomson PJ AD - Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K. FAU - Hammond, Sean AU - Hammond S AD - Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K. AD - ApconiX, Alderley Park, Alderley Edge, Cheshire SK10 4TG, U.K. FAU - Zhang, Eunice AU - Zhang E AD - Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K. FAU - Alfirevic, Ana AU - Alfirevic A AD - Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K. FAU - Sukasem, Chonlaphat AU - Sukasem C AD - Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K. AD - Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. AD - Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok 10400, Thailand. FAU - Naisbitt, Dean J AU - Naisbitt DJ AUID- ORCID: 0000-0003-4107-7832 AD - Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K. FAU - Pirmohamed, Munir AU - Pirmohamed M AD - Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K. LA - eng GR - G0700654/MRC_/Medical Research Council/United Kingdom GR - MR/R009635/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230419 PL - United States TA - Chem Res Toxicol JT - Chemical research in toxicology JID - 8807448 RN - 0 (HLA-DRB1 Chains) RN - 33CM23913M (Carbamazepine) RN - 0 (Anticonvulsants) RN - 0 (HLA Antigens) RN - 0 (HLA-B Antigens) SB - IM MH - Humans MH - CD8-Positive T-Lymphocytes MH - HLA-DRB1 Chains/genetics MH - Carbamazepine/adverse effects MH - Anticonvulsants/adverse effects MH - *Drug Hypersensitivity/genetics MH - HLA Antigens MH - *Stevens-Johnson Syndrome/genetics MH - CD4-Positive T-Lymphocytes MH - HLA-B Antigens PMC - PMC10189794 COIS- The authors declare no competing financial interest. EDAT- 2023/04/19 12:42 MHDA- 2023/05/16 06:42 PMCR- 2023/05/17 CRDT- 2023/04/19 11:34 PHST- 2023/05/16 06:42 [medline] PHST- 2023/04/19 12:42 [pubmed] PHST- 2023/04/19 11:34 [entrez] PHST- 2023/05/17 00:00 [pmc-release] AID - 10.1021/acs.chemrestox.2c00414 [doi] PST - ppublish SO - Chem Res Toxicol. 2023 May 15;36(5):757-768. doi: 10.1021/acs.chemrestox.2c00414. Epub 2023 Apr 19.