Characterization of Healthy Donor-Derived T-Cell Responses Specific to Telaprevir Diastereomers
| Autor: | Khetam Alhilali, Jan Snoeys, Arun Tailor, Andrew Gibson, Mario Monshouwer, B. Kevin Park, Dean J. Naisbitt, Zaid Al-Attar, Xiaoli Meng |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
CD4-Positive T-Lymphocytes
Cytotoxicity Immunologic 0301 basic medicine T cell Cell Culture Techniques CD8-Positive T-Lymphocytes Pharmacology Toxicology Peripheral blood mononuclear cell Telaprevir 03 medical and health sciences Chemokine receptor 0302 clinical medicine medicine Humans Cytotoxic T cell Cells Cultured Antigen Presentation biology Chemistry T-cell receptor Stereoisomerism Healthy Volunteers Clone Cells 030104 developmental biology medicine.anatomical_structure Granzyme Leukocytes Mononuclear biology.protein Inflammation Mediators Oligopeptides 030217 neurology & neurosurgery CD8 medicine.drug |
| Zdroj: | TOXICOLOGICAL SCIENCES |
| ISSN: | 1096-0929 1096-6080 |
| Popis: | Telaprevir, a protease inhibitor, was used alongside PEGylated interferon-α and ribavirin to treat hepatitis C viral infections. The triple regimen proved successful; however, the appearance of severe skin reactions alongside competition from newer drugs restricted its use. Skin reactions presented with a delayed onset indicative of a T-cell mediated reaction. Thus, the aim of this study was to investigate whether telaprevir and/or its diastereomer, which is generated in humans, activates T-cells. Telaprevir in its S-configured therapeutic form and the R-diastereomer were cultured directly with peripheral blood mononuclear cells from healthy donors prior to the generation of T-cell clones by serial dilution. Drug-specific CD4+ and CD8+ T-cell clones responsive to telaprevir and the R-diastereomer were generated and characterized in terms of phenotype and function. The clones proliferated with telaprevir and diastereomer concentrations of 5-20 µM and secreted IFN-γ, IL-13, and granzyme B. In contrast, the telaprevir M11 metabolite did not stimulate T-cells. The CD8+ T-cell response was MHC I-restricted and dependent on the presence of soluble drug. Flow cytometric analysis showed that clones expressed chemokine receptors CCR4 (skin homing) and CXCR3 (migration to peripheral tissue) and 1 of 3 distinct TCR Vβs; TCR Vβ 2, 5.1, or 22. These data show the propensity of both R- and S-forms of telaprevir to generate skin-homing cytotoxic T-cells that may induce the adverse reactions observed in human patients. |
| Databáze: | OpenAIRE |
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