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Shared Clavulanate and Tazobactam Antigenic Determinants Activate T-Cells from Hypersensitive Patients.
Ariza, Adriana; Jaruthamsophon, Kanoot; Meng, Xiaoli; Labella, Marina; Adair, Kareena; Tailor, Arun; Sukasem, Chonlaphat; Whitaker, Paul; Peckham, Daniel; Pirmohamed, Munir; Torres, María José; Naisbitt, Dean John.
Afiliación
  • Ariza A; Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain.
  • Jaruthamsophon K; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K.
  • Meng X; Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
  • Labella M; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K.
  • Adair K; Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, 29009 Málaga, Spain.
  • Tailor A; Allergy Unit, Hospital Regional Universitario de Málaga, 29009 Málaga, Spain.
  • Sukasem C; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K.
  • Whitaker P; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K.
  • Peckham D; Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
  • Pirmohamed M; Bradford Teaching Hospitals NHS Trust, Bradford BD9 6DA, U.K.
  • Torres MJ; Regional Adult Cystic Fibrosis Unit, St James's University Hospital, Leeds LS9 7TF, U.K.
  • Naisbitt DJ; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool L69 3GE, U.K.
Chem Res Toxicol ; 35(11): 2122-2132, 2022 11 21.
Article en En | MEDLINE | ID: mdl-36137197
ß-Lactamase inhibitors such as clavulanic acid and tazobactam were developed to overcome ß-lactam antibiotic resistance. Hypersensitivity reactions to these drugs have not been studied in detail, and the antigenic determinants that activate T-cells have not been defined. The objectives of this study were to (i) characterize clavulanate- and tazobactam-responsive T-cells from hypersensitive patients, (ii) explore clavulanate and tazobactam T-cell crossreactivity, and (iii) define the antigenic determinants that contribute to T-cell reactivity. Antigen specificity, pathways of T-cell activation, and crossreactivity with clavulanate- and tazobactam-specific T-cell clones were assessed by proliferation and cytokine release assays. Antigenic determinants were analyzed by mass spectrometry-based proteomics methods. Clavulanate- and tazobactam-responsive CD4+ T-cell clones were stimulated to proliferate and secrete IFN-γ in an MHC class II-restricted and dose-dependent manner. T-cell activation with clavulanate- and tazobactam was dependent on antigen presenting cells because their fixation prevented the T-cell response. Strong crossreactivity was observed between clavulanate- and tazobactam-T-cells; however, neither drug activated ß-lactam antibiotic-responsive T-cells. Mass spectrometric analysis revealed that both compounds form multiple antigenic determinants with lysine residues on proteins, including an overlapping aldehyde and hydrated aldehyde adduct with mass additions of 70 and 88 Da, respectively. Collectively, these data show that although clavulanate and tazobactam are structurally distinct, the antigenic determinants formed by both drugs overlap, which explains the observed T-cell cross-reactivity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T / Inhibidores de beta-Lactamasas Límite: Humans Idioma: En Revista: Chem Res Toxicol Asunto de la revista: TOXICOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T / Inhibidores de beta-Lactamasas Límite: Humans Idioma: En Revista: Chem Res Toxicol Asunto de la revista: TOXICOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos