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Shared Clavulanate and Tazobactam Antigenic Determinants Activate T-Cells from Hypersensitive Patients.

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dc.contributor.authorAriza, Adriana
dc.contributor.authorJaruthamsophon, Kanoot
dc.contributor.authorMeng, Xiaoli
dc.contributor.authorLabella, Marina
dc.contributor.authorAdair, Kareena
dc.contributor.authorTailor, Arun
dc.contributor.authorSukasem, Chonlaphat
dc.contributor.authorWhitaker, Paul
dc.contributor.authorPeckham, Daniel
dc.contributor.authorPirmohamed, Munir
dc.contributor.authorTorres, María José
dc.contributor.authorNaisbitt, Dean John
dc.date.accessioned2024-02-27T15:24:00Z
dc.date.available2024-02-27T15:24:00Z
dc.date.issued2022-09-22
dc.description.abstractβ-Lactamase inhibitors such as clavulanic acid and tazobactam were developed to overcome β-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 β-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.
dc.format.number11es_ES
dc.format.page2122-2132es_ES
dc.format.volume35es_ES
dc.identifier.doi10.1021/acs.chemrestox.2c00231
dc.identifier.e-issn1520-5010es_ES
dc.identifier.journalChemical research in toxicologyes_ES
dc.identifier.otherhttp://hdl.handle.net/10668/22586
dc.identifier.pubmedID36137197es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/18821
dc.language.isoeng
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAttribution 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subject.meshHumans
dc.subject.meshClavulanic Acid
dc.subject.meshTazobactam
dc.subject.meshEpitopes
dc.subject.meshT-Lymphocytes
dc.subject.meshbeta-Lactamase Inhibitors
dc.subject.meshAnti-Bacterial Agents
dc.subject.meshAldehydes
dc.titleShared Clavulanate and Tazobactam Antigenic Determinants Activate T-Cells from Hypersensitive Patients.
dc.typeresearch article
dc.type.hasVersionVoR
dspace.entity.typePublication
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