Journal
TOXICOLOGICAL SCIENCES
Volume 179, Issue 1, Pages 95-107Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfaa157
Keywords
Tolvaptan; drug-induced liver injury; T-lymphocytes; ADPKD; human
Categories
Funding
- Otsuka Pharmaceutical Development & Commercialization (OPDC)
- Medical Research Council [MR/R009635/1]
- Centre for Drug Safety Science [MR/l006758]
- MRC [MR/R009635/1] Funding Source: UKRI
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Exposure to tolvaptan is associated with a significant risk of liver injury, potentially due to an adaptive immune attack. The study suggests that tolvaptan and metabolite-specific T cells may be candidate effector cells in such injury.
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 18months 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 drugspecific 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-c, 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 4h 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.
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