Elucidating CD4+ and CD8+ T-cell involvement in patients with vancomycin-induced DRESS
Joshua Gardner1, Silvia Martinez-Rivera2, James Line1
1Department of Pharmacology and Therapeutics, Centre for Drug Safety Science, The University of Liverpool, Liverpool L69 3GE, United Kingdom.
Abstract:
Vancomycin, a glycopeptide antibiotic used to treat severe Gram-positive bacterial infections, is associated with the development of drug reaction with eosinophilia and systemic symptoms (DRESS) in individuals expressing HLA-A*32:01. Previous studies have identified the potential role of T-cells using HLA-A*32:01-positive healthy donor models. However, DRESS pathogenesis remains poorly defined, and a deeper mechanistic understanding is required to aid the diagnosis and prediction of vancomycin-induced DRESS. The present study aims to elucidate CD4+ and CD8+ T-cell involvement within the pathogenesis of vancomycin-induced DRESS following the isolation and functional study of cloned T-cells from hypersensitive patients. CD4+ and CD8+ vancomycin-responsive T-cell clones (TCCs) were generated by serial dilution from peripheral blood mononuclear cells collected from suspected vancomycin-DRESS patients. Functionality of drug-responsive TCCs was assessed using T-cell proliferation ([3H]-thymidine). Cytokine analysis was performed using intracellular cytokine staining, enzyme-linked immunospot assay, and LEGENDplex immunoassays. Vancomycin-responsive TCCs expressing CD4+ and CD8+ phenotypes were successfully generated from suspected vancomycin-DRESS patients (n = 3). CD45RO+ memory T-cells were the primary activated population, with both CD4+ and CD8+ T-cells associated with the release of IFN-γ, IL-5, IL-13, granzyme B, and perforin. Vancomycin-responsive CD4+ and CD8+ T-cells are activated by direct, pharmacological interactions, with antigen presentation possible through HLA class I and HLA class II molecules. This study provides in vitro evidence for the dual role of antigen-specific CD4+ and CD8+ T-cells within the pathogenesis of vancomycin-induced DRESS. This has been demonstrated following the generation of cloned T-cells with strong vancomycin specificity from patients presenting with vancomycin-DRESS and positive for expression of HLA-A*32:01.
Insights
Vancomycin-induced DRESS involves both CD4+ and CD8+ T-cells, which are activated by direct drug interactions. This study clarifies the dual T-cell role in DRESS pathogenesis for better diagnosis and prediction.
Area of Science:
- Immunology
- Pharmacology
- Genetics
Background:
- Vancomycin-induced DRESS is a severe reaction linked to HLA-A*32:01.
- The precise mechanisms of DRESS pathogenesis are not fully understood.
- T-cell involvement has been suggested but requires deeper mechanistic insight.
Purpose of the Study:
- To investigate the role of CD4+ and CD8+ T-cells in vancomycin-induced DRESS.
- To functionally characterize vancomycin-specific T-cell clones from hypersensitive patients.
- To elucidate the mechanisms underlying T-cell activation in DRESS.
Main Methods:
- Generation of vancomycin-responsive CD4+ and CD8+ T-cell clones (TCCs) from patients.
- Assessment of TCC functionality via [3H]-thymidine proliferation assays.
- Cytokine analysis using intracellular cytokine staining, ELISpot, and LEGENDplex immunoassays.
Main Results:
- Successfully generated CD4+ and CD8+ vancomycin-responsive TCCs from DRESS patients.
- Identified CD45RO+ memory T-cells as the primary activated population.
- Both CD4+ and CD8+ T-cells released key cytokines (IFN-γ, IL-5, IL-13) and cytotoxic molecules (granzyme B, perforin).
Conclusions:
- Vancomycin-responsive T-cells are activated through direct drug interaction and HLA class I/II antigen presentation.
- This study provides in vitro evidence for a dual role of CD4+ and CD8+ T-cells in vancomycin-induced DRESS pathogenesis.
- Findings support the importance of T-cell specificity and HLA-A*32:01 in DRESS development.
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