期刊
TOXICOLOGICAL SCIENCES
卷 183, 期 1, 页码 139-153出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfab084
关键词
drug hypersensitivity; vancomycin; T cells; HLA
类别
资金
- BBSRC/GSK Industrial Partnership award [BB/R008108/1]
- MRC Centre for Drug Safety Science [G0700654]
- MRC [MR/L006758/1] Funding Source: UKRI
This study demonstrates the importance of HLA-A*32:01 expression in priming T cells with vancomycin, leading to stronger responses. CD8+ T cells are activated through a direct binding interaction with vancomycin, with evidence of cross-reactivity with other antibiotics like teicoplanin.
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 naive 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 naive T cells and vancomycin for 2weeks. On day 14, cells were restimulated with vancomycin and T-cell proliferation was assessed by [H-3]-thymidine incorporation. Vancomycin-specific TCC were generated by serial dilution and repetitive mitogen stimulation. Naive 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-gamma, 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 naive 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.
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