{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:32:43Z","timestamp":1790652763627,"version":"4.1.0"},"reference-count":21,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":190,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["93647"],"award-info":[{"award-number":["93647"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:p>\n                    The mechanism of idiosyncratic drug\u2010induced liver injury (IDILI) remains poorly understood, to a large degree because of the lack of a valid animal model. Recently, we reported an animal model in which treatment of female C57BL\/6 mice with amodiaquine (AQ) resulted in mild liver injury with a delayed onset and resolution despite continued treatment. Such adaptation is a common outcome in the IDILI caused by drugs that can cause liver failure. We had hypothesized that most IDILI is immune\u2010mediated and adaptation represents immune tolerance. In this study we found that AQ treatment of Cbl\u2010b\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    and PD\u20101\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice, which have impaired immune tolerance, resulted in a slightly greater injury. Cotreatment of C57BL\/6 with AQ and anti\u2010CTLA4 also resulted in a greater increase in ALT than treatment with AQ alone; however, these mice also had an increase in T regulatory (Treg) cells and T helper cells expressing PD\u20101 and CTLA4. The increase in these cells implies the induction of immune tolerance, and the alanine aminotransferase (ALT) activity in these mice returned to normal despite continued treatment. Cotreatment of PD\u20101\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice with anti\u2010CTLA4 antibody and AQ resulted in the greatest increase in ALT (200\u2010300 U\/L), and necroinflammatory responses characterized by portal infiltration of lymphocytes with interface hepatitis. The lymphocyte infiltration included T and B cells, and the CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells produced perforin and granzyme. In addition, the ALT activity in PD\u20101\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice cotreated with anti\u2010CTLA4 antibody and AQ did not return to normal, as it had in other mice.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : We report here the first animal model of IDILI that is similar to the IDILI that occurs in humans, and it was accomplished by inhibiting immune tolerance. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2015;61:1332\u20131342)\n                  <\/jats:p>","DOI":"10.1002\/hep.27549","type":"journal-article","created":{"date-parts":[[2014,10,6]],"date-time":"2014-10-06T02:17:06Z","timestamp":1412561826000},"page":"1332-1342","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":140,"title":["Treatment of PD\u20101\u2212\/\u2212 mice with amodiaquine and anti\u2010CTLA4 leads to liver injury similar to idiosyncratic liver injury in patients"],"prefix":"10.1097","volume":"61","author":[{"given":"Imir G.","family":"Metushi","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine,University of Toronto,Toronto,Ontario,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Anthony","family":"Hayes","sequence":"additional","affiliation":[{"name":"Department of Pathobiology,University of Guelph,Guelph,Ontario,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Uetrecht","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine,University of Toronto,Toronto,Ontario,Canada"},{"name":"Department of Pharmaceutical Sciences, Faculty of Pharmacy,University of Toronto,Toronto,Ontario,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2015,2,23]]},"reference":[{"key":"hep27549-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"947","DOI":"10.7326\/0003-4819-137-12-200212170-00007","article-title":"Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States","volume":"137","year":"2002","journal-title":"Ann Intern Med"},{"key":"hep27549-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/pds.1211","article-title":"Hy's law: predicting serious hepatotoxicity","volume":"15","year":"2006","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"hep27549-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/B978-0-12-398339-8.00003-3","article-title":"Animal models of idiosyncratic drug reactions","volume":"63","year":"2012","journal-title":"Adv Pharmacol"},{"key":"hep27549-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1124\/pr.113.007450","article-title":"Idiosyncratic adverse drug reactions: current concepts","volume":"65","year":"2013","journal-title":"Pharmacol Rev"},{"key":"hep27549-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/clpt.2010.355","article-title":"A fresh look at the mechanism of isoniazid\u2010induced hepatotoxicity","volume":"89","year":"2011","journal-title":"Clin Pharmacol Ther"},{"key":"hep27549-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/ng.379","article-title":"HLA\u2010B*5701 genotype is a major determinant of drug\u2010induced liver injury due to flucloxacillin","volume":"41","year":"2009","journal-title":"Nat Genet"},{"key":"hep27549-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/sj.tpj.6500458","article-title":"Genome\u2010wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis","volume":"8","year":"2008","journal-title":"Pharmacogenom J"},{"key":"hep27549-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1038\/ng.632","article-title":"A genome\u2010wide study identifies HLA alleles associated with lumiracoxib\u2010related liver injury","volume":"42","year":"2010","journal-title":"Nat Genet"},{"key":"hep27549-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"243","DOI":"10.2165\/11586600-000000000-00000","article-title":"Evaluation of drug\u2010induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery","volume":"34","year":"2011","journal-title":"Drug Saf"},{"key":"hep27549-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/01926230590888306","article-title":"Idiosyncratic liver injury: challenges and approaches","volume":"33","year":"2005","journal-title":"Toxicol Pathol"},{"key":"hep27549-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1034\/j.1600-0528.2002.017412.x","article-title":"The liver as a site of T\u2010cell apoptosis: graveyard, or killing field?","volume":"174","year":"2000","journal-title":"Immunol Rev"},{"key":"hep27549-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1158\/0008-5472.CAN-09-4076","article-title":"Cbl\u2010b and itch: key regulators of peripheral T\u2010cell tolerance","volume":"70","year":"2010","journal-title":"Cancer Res"},{"key":"hep27549-bib-0013-20241017","article-title":"Isoniazid\u2010induced liver injury and immune response in mice","year":"2013","journal-title":"J Immunotoxicol"},{"key":"hep27549-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"hep27549-bib-0015-20241017","first-page":"1","article-title":"Development of a novel mouse model of amodiaquine\u2010induced liver injury with a delayed onset","year":"2014","journal-title":"J Immunotoxicol"},{"key":"hep27549-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"801","DOI":"10.7326\/0003-4819-104-6-801","article-title":"Machayekhy JP, Feldmann G, et al. 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