Drug-specific T-cell responses in patients with liver injury following treatment with the BACE inhibitor atabecestat

Thomson, Paul J ORCID: 0000-0001-5431-0459, Kafu, Laila, Meng, Xiaoli ORCID: 0000-0002-7774-2075, Snoeys, Jan, De Bondt, An, De Maeyer, Dries, Wils, Hans, Leclercq, Laurent, Vinken, Petra and Naisbitt, Dean J (2021) Drug-specific T-cell responses in patients with liver injury following treatment with the BACE inhibitor atabecestat. ALLERGY, 76 (6). pp. 1825-1835.

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Abstract

<h4>Background</h4>Atabecestat is an orally administered BACE inhibitor developed to treat Alzheimer's disease. Elevations in hepatic enzymes were detected in a number of in trial patients, which resulted in termination of the drug development programme. Immunohistochemical characterization of liver tissue from an index case of atabecestat-mediated liver injury revealed an infiltration of T-lymphocytes in areas of hepatocellular damage. This coupled with the fact that liver injury had a delayed onset suggests that the adaptive immune system may be involved in the pathogenesis. The aim of this study was to generate and characterize atabecestat(metabolite)-responsive T-cell clones from patients with liver injury.<h4>Methods</h4>Peripheral blood mononuclear cells were cultured with atabecestat and its metabolites (diaminothiazine [DIAT], N-acetyl DIAT & epoxide) and cloning was attempted in a number of patients. Atabecestat(metabolite)-responsive clones were analysed in terms of T-cell phenotype, function, pathways of T-cell activation and cross-reactivity with structurally related compounds.<h4>Results</h4>CD4⁺ T-cell clones activated with the DIAT metabolite were detected in 5 out of 8 patients (up to 4.5% cloning efficiency). Lower numbers of CD4⁺ and CD8⁺ clones displayed reactivity against atabecestat. Clones proliferated and secreted IFN-γ, IL-13 and cytolytic molecules following atabecestat or DIAT stimulation. Certain atabecestat and DIAT-responsive clones cross-reacted with N-acetyl DIAT; however, no cross-reactivity was observed between atabecestat and DIAT. CD4⁺ clones were activated through a direct, reversible compound-HLA class II interaction with no requirement for protein processing.<h4>Conclusion</h4>The detection of atabecestat metabolite-responsive T-cell clones activated via a pharmacological interactions pathway in patients with liver injury is indicative of an immune-based mechanism for the observed hepatic enzyme elevations.

Item Type:	Article
Uncontrolled Keywords:	drug&#8208, induced liver injury, human, immune system, T&#8208, lymphocytes
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 14:31
Last Modified:	18 Jan 2023 21:37
DOI:	10.1111/all.14652
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3128547