Hammond, Sean, Gibson, Andrew, Jaruthamsophon, Kanoot ORCID: 0000-0003-1563-0024, Roth, Sharin, Mosedale, Merrie and Naisbitt, Dean J
(2021)
Shedding Light on Drug-Induced Liver Injury: Activation of T Cells From Drug Naive Human Donors With Tolvaptan and a Hydroxybutyric Acid Metabolite.
TOXICOLOGICAL SCIENCES, 179 (1).
pp. 95-107.
Text
TOXSCI-20-0422.R2_Proof_hi.pdf - Author Accepted Manuscript Download (2MB) | Preview |
Abstract
Exposure to tolvaptan is associated with a significant risk of liver injury in a small fraction of patients with autosomal dominant polycystic kidney disease. The observed delayed onset of liver injury of between 3 and 18 months after commencing tolvaptan treatment, along with rapid recurrence of symptoms following re-challenge is indicative of an adaptive immune attack. This study set out to assess the intrinsic immunogenicity of tolvaptan and pathways of drug-specific T-cell activation using in vitro cell culture platforms. Tolvaptan (n = 7), as well as oxybutyric (DM-4103, n = 1) and hydroxybutyric acid (DM-4107, n = 18) metabolite-specific T-cell clones were generated from tolvaptan naive healthy donor peripheral blood mononuclear cells. Tolvaptan and DM-4103 T-cell clones could also be activated with DM-4107, whereas T-cell clones originally primed with DM-4107 were highly specific to this compound. A signature cytokine profile (IFN-γ, IL-13, granzyme B, and perforin) for almost all T-cell clones was identified. Mechanistically, compound-specific T-cell clone activation was dependent on the presence of soluble drug and could occur within 4 h of drug exposure, ruling out a classical hapten mechanism. However, antigen processing dependence drug presentation was indicated in many T-cell clones. Collectively these data show that tolvaptan-associated liver injury may be attributable to an adaptive immune attack upon the liver, with tolvaptan- and metabolite-specific T cells identified as candidate effector cells in such etiology.
Item Type: | Article |
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Uncontrolled Keywords: | Tolvaptan, drug-induced liver injury, T-lymphocytes, ADPKD, human |
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: | 02 Jul 2021 15:23 |
Last Modified: | 18 Jan 2023 21:37 |
DOI: | 10.1093/toxsci/kfaa157 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3128546 |