{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:00:28Z","timestamp":1788872428137,"version":"build-2803163510"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":160,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100006955","name":"Office of Extramural Research, National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:p>\n                    Clinical evidence suggests that many cases of serious idiosyncratic drug\u2010induced liver injury are mediated by the adaptive immune system in response to hepatic drug\u2010protein adducts, also referred to as \u201cdrug\u2010induced allergic hepatitis\u201d; but detailed mechanistic proof has remained elusive due to the lack of animal models. We have hypothesized that drug\u2010induced allergic hepatitis is as rare in animals as it is in humans due at least in part to the tolerogenic nature of the liver. We provide evidence that immune tolerance can be overcome in a murine model of halothane\u2010induced liver injury initiated by trifluoroacetylated protein adducts of halothane formed in the liver. Twenty\u2010four hours after female Balb\/cJ mice were initially treated with halothane, perivenous necrosis and an infiltration of CD11b\n                    <jats:sup>+<\/jats:sup>\n                    Gr\u20101\n                    <jats:sup>high<\/jats:sup>\n                    cells were observed in the liver. Further study revealed a subpopulation of myeloid\u2010derived suppressor cells within the CD11b\n                    <jats:sup>+<\/jats:sup>\n                    Gr\u20101\n                    <jats:sup>high<\/jats:sup>\n                    cell fraction that inhibited the proliferation of both CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. When CD11b\n                    <jats:sup>+<\/jats:sup>\n                    Gr\u20101\n                    <jats:sup>high<\/jats:sup>\n                    cells were depleted from the liver with Gr\u20101 antibody treatment, enhanced liver injury was observed at 9 days after halothane rechallenge. Toxicity was associated with increased serum levels of interleukin\u20104 and immunoglobulins G1 and E directed against hepatic trifluoroacetylated protein adducts, as well as increased hepatic infiltration of eosinophils and CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, all features of an allergic reaction. When hepatic CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells were depleted 5 days after halothane rechallenge, trifluoroacetylated protein adduct\u2013specific serum immunoglobulin and hepatotoxicity were reduced.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : Our data provide a rational approach for developing animal models of drug\u2010induced allergic hepatitis mediated by the adaptive immune system and suggest that impaired liver tolerance may predispose patients to this disease. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2015;62:546\u2013557\n                  <\/jats:p>","DOI":"10.1002\/hep.27764","type":"journal-article","created":{"date-parts":[[2015,2,24]],"date-time":"2015-02-24T19:03:09Z","timestamp":1424804589000},"page":"546-557","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":59,"title":["Drug\u2010induced allergic hepatitis develops in mice when myeloid\u2010derived suppressor cells are depleted prior to halothane treatment"],"prefix":"10.1097","volume":"62","author":[{"given":"Mala","family":"Chakraborty","sequence":"first","affiliation":[{"name":"Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology,National Heart, Lung and Blood Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron M.","family":"Fullerton","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology,National Heart, Lung and Blood Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenrick","family":"Semple","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology,National Heart, Lung and Blood Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynette S.","family":"Chea","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology,National Heart, Lung and Blood Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Proctor","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology,National Heart, Lung and Blood Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Bourdi","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology,National Heart, Lung and Blood Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Kleiner","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology,National Cancer Institute,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangbin","family":"Zeng","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology,National Heart, Lung and Blood Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline M.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology,National Heart, Lung and Blood Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep K.","family":"Dagur","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart,Lung and Blood Institute,National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia D.","family":"Berkson","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology,National Heart, Lung and Blood Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy P.","family":"Reilly","sequence":"additional","affiliation":[{"name":"Exploratory Clinical & Translational Research,Bristol\u2010Myers Squibb Company,Princeton,NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance R.","family":"Pohl","sequence":"additional","affiliation":[{"name":"Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology,National Heart, Lung and Blood Institute, National Institutes of Health,Bethesda,MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2015,3,25]]},"reference":[{"key":"hep27764-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 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