{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T12:04:37Z","timestamp":1770984277744,"version":"3.50.1"},"reference-count":40,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2020,10,20]],"date-time":"2020-10-20T00:00:00Z","timestamp":1603152000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R009635\/1"],"award-info":[{"award-number":["MR\/R009635\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Centre for Drug Safety Science","award":["MR\/l006758"],"award-info":[{"award-number":["MR\/l006758"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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\u2009months 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\u2009=\u20097), as well as oxybutyric (DM-4103, n\u2009=\u20091) and hydroxybutyric acid (DM-4107, n\u2009=\u200918) 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-\u03b3, 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\u2009h 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.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa157","type":"journal-article","created":{"date-parts":[[2020,10,7]],"date-time":"2020-10-07T11:59:28Z","timestamp":1602071968000},"source":"Crossref","is-referenced-by-count":3,"title":["Shedding Light on Drug-Induced Liver Injury: Activation of T Cells From Drug Naive Human Donors With Tolvaptan and a Hydroxybutyric Acid Metabolite"],"prefix":"10.1093","author":[{"given":"Sean","family":"Hammond","sequence":"first","affiliation":[{"name":"MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Gibson","sequence":"additional","affiliation":[{"name":"MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanoot","family":"Jaruthamsophon","sequence":"additional","affiliation":[{"name":"MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, UK"},{"name":"Department of Pathology, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharin","family":"Roth","sequence":"additional","affiliation":[{"name":"Otsuka Pharmaceutical Dev. & Comm., Inc., Research Blvd, Rockville, Maryland 20882"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1968-6666","authenticated-orcid":false,"given":"Merrie","family":"Mosedale","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4107-7832","authenticated-orcid":false,"given":"Dean J","family":"Naisbitt","sequence":"additional","affiliation":[{"name":"MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,10,20]]},"reference":[{"key":"2020120503265992500_kfaa157-B1","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1002\/eji.201142159","article-title":"Avidity determines T-cell reactivity in abacavir hypersensitivity","volume":"42","author":"Adam","year":"2012","journal-title":"Eur. 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