Deciphering Adverse Drug Reactions: In Vitro Priming and Characterization of Vancomycin-Specific T Cells From Healthy Donors Expressing HLA-A*32:01

Ogese, Monday O ORCID: 0000-0002-1873-4032, Lister, Adam, Gardner, Joshua, Meng, Xiaoli ORCID: 0000-0002-7774-2075, Alfirevic, Ana ORCID: 0000-0002-2801-9817, Pirmohamed, Munir ORCID: 0000-0002-7534-7266, Park, B Kevin ORCID: 0000-0001-8384-824X and Naisbitt, Dean J (2021) Deciphering Adverse Drug Reactions: In Vitro Priming and Characterization of Vancomycin-Specific T Cells From Healthy Donors Expressing HLA-A*32:01. TOXICOLOGICAL SCIENCES, 183 (1). pp. 139-153.

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Abstract

Drug rash with eosinophilia with systemic symptoms (DRESS) is a serious adverse event associated with use of the glycopeptide antibiotic vancomycin. Vancomycin-induced drug rash with eosinophilia with systemic symptoms is associated with the expression of human leukocyte antigen (HLA)-A*32:01, suggesting that the drug interacts with this HLA to activate CD8+ T cells. The purpose of this study was to utilize peripheral blood mononuclear cell from healthy donors to: (1) investigate whether expression of HLA-A*32:01 is critical for the priming naïve of T cells with vancomycin and (2) generate T-cell clones (TCC) to determine whether vancomycin exclusively activates CD8+ T cells and to define cellular phenotype, pathways of drug presentation and cross-reactivity. Dendritic cells were cultured with naïve T cells and vancomycin for 2 weeks. On day 14, cells were restimulated with vancomycin and T-cell proliferation was assessed by [3H]-thymidine incorporation. Vancomycin-specific TCC were generated by serial dilution and repetitive mitogen stimulation. Naïve T cells from HLA-A*02:01 positive and negative donors were activated with vancomycin; however the strength of the induced response was significantly stronger in donors expressing HLA-A*32:01. Vancomycin-responsive CD4+ and CD8+ TCC from HLA-A*32:01+ donors expressed high levels of CXCR3 and CCR4, and secreted IFN-γ, IL-13, and cytolytic molecules. Activation of CD8+ TCC was HLA class I-restricted and dependent on a direct vancomycin HLA binding interaction with no requirement for processing. Several TCC displayed cross-reactivity with teicoplanin and daptomycin. To conclude, this study provides evidence that vancomycin primes naïve T cells from healthy donors expressing HLA-A*32:01 through a direct pharmacological binding interaction. Cross-reactivity of CD8+ TCC with teicoplanin provides an explanation for the teicoplanin reactions observed in vancomycin hypersensitive patients.

Item Type:	Article
Uncontrolled Keywords:	drug hypersensitivity, vancomycin, T cells, HLA
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:	05 Jul 2021 14:20
Last Modified:	18 Jan 2023 21:37
DOI:	10.1093/toxsci/kfab084
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3128549