Characterization of Healthy Donor-Derived T-Cell Responses Specific to Telaprevir Diastereomers

Alhilali, Khetam Ali, Al-Attar, Zaid, Gibson, Andrew, Tailor, Arun ORCID: 0000-0002-9698-3480, Meng, Xiaoli ORCID: 0000-0002-7774-2075, Monshouwer, Mario, Snoeys, Jan, Park, B Kevin ORCID: 0000-0001-8384-824X and Naisbitt, Dean J (2019) Characterization of Healthy Donor-Derived T-Cell Responses Specific to Telaprevir Diastereomers. TOXICOLOGICAL SCIENCES, 168 (2). pp. 597-609.

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Official URL: http://dx.doi.org/10.1093/toxsci/kfz007

Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	drug hypersensitivity, T-cells, immune system
Depositing User:	Symplectic Admin
Date Deposited:	10 Sep 2019 07:21
Last Modified:	19 Jan 2023 00:55
DOI:	10.1093/toxsci/kfz007
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3035092