{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T23:04:14Z","timestamp":1793747054582,"version":"4.6.1"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T00:00:00Z","timestamp":1472688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The etiopathogenesis of autoimmune hepatitis (AIH) remains poorly understood. In this study, we sought to develop an animal model of human AIH to gain insight into the immunological mechanisms driving this condition. C57BL\/6 mice were i.v. injected with adeno-associated viral vectors encoding murine IL-12 or luciferase under the control of a liver-specific promoter. Organ histology, response to immunosuppressive therapy, and biochemical and immunological parameters, including Ag-specific humoral and cellular response, were analyzed. Mechanistic studies were carried out using genetically modified mice and depletion of lymphocyte subpopulations. Adeno-associated virus IL-12\u2013treated mice developed histological, biochemical, and immunological changes resembling type 1 AIH, including marked and persistent liver mononuclear cell infiltration, hepatic fibrosis, hypergammaglobulinemia, anti-nuclear and anti\u2013smooth muscle actin Abs, and disease remission with immunosuppressive drugs. Interestingly, transgenic IL-12 was short-lived, but endogenous IL-12 expression was induced, and both IL-12 and IFN-\u03b3 remained elevated during the entire study period. IFN-\u03b3 was identified as an essential mediator of liver damage, and CD4 and CD8 T cells but not NK, NKT, or B cells were essential executors of hepatic injury. Furthermore, both MHC class I and MHC class II expression was upregulated at the hepatocellular membrane, and induction of autoreactive liver-specific T cells was detected. Remarkably, although immunoregulatory mechanisms were activated, they only partially mitigated liver damage. Thus, low and transient expression of transgenic IL-12 in hepatocytes causes loss of tolerance to hepatocellular Ags, leading to chronic hepatitis resembling human AIH type 1. This model provides a practical tool to explore AIH pathogenesis and novel therapies.<\/jats:p>","DOI":"10.4049\/jimmunol.1600228","type":"journal-article","created":{"date-parts":[[2016,8,11]],"date-time":"2016-08-11T02:19:37Z","timestamp":1470881977000},"page":"2145-2156","source":"Crossref","is-referenced-by-count":28,"title":["Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis"],"prefix":"10.1093","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9839-1411","authenticated-orcid":false,"given":"Irene","family":"Gil-Farina","sequence":"first","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra , 31008 Pamplona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4460-6472","authenticated-orcid":false,"given":"Marianna","family":"Di Scala","sequence":"additional","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra , 31008 Pamplona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Salido","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n Mixta Hospital Universitario de Canarias\u2013Universidad de La Laguna, Facultad de Medicina, Universidad de La Laguna , 38071 Santa Cruz de Tenerife,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-3126","authenticated-orcid":false,"given":"Esperanza","family":"L\u00f3pez-Franco","sequence":"additional","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra , 31008 Pamplona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefania","family":"Rodr\u00edguez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra , 31008 Pamplona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Blasi","sequence":"additional","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra , 31008 Pamplona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juana","family":"Merino","sequence":"additional","affiliation":[{"name":"University Clinic of Navarra, University of Navarra , 31008 Pamplona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9461-020X","authenticated-orcid":false,"given":"Rafael","family":"Aldabe","sequence":"additional","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra , 31008 Pamplona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Prieto","sequence":"additional","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra , 31008 Pamplona,","place":["Spain"]},{"name":"University Clinic of Navarra, University of Navarra , 31008 Pamplona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1600-4562","authenticated-orcid":false,"given":"Gloria","family":"Gonzalez-Aseguinolaza","sequence":"additional","affiliation":[{"name":"Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, Health Research Institute of Navarra , 31008 Pamplona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,9,15]]},"reference":[{"key":"2025030617482501200_r1","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1002\/hep.23584","article-title":"Diagnosis and management of autoimmune hepatitis","volume":"51","author":"Manns","year":"2010","journal-title":"Hepatology"},{"key":"2025030617482501200_r2","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jaut.2015.10.006","article-title":"The clinical phenotypes of autoimmune hepatitis: a comprehensive review","volume":"66","author":"Wang","year":"2016","journal-title":"J. Autoimmun."},{"key":"2025030617482501200_r3","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/hep.1840110106","article-title":"Experimental autoimmune hepatitis: disease induction, time course and T-cell reactivity","volume":"11","author":"Lohse","year":"1990","journal-title":"Hepatology"},{"key":"2025030617482501200_r4","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.autrev.2005.01.005","article-title":"T cell immunity in autoimmune hepatitis","volume":"4","author":"Ichiki","year":"2005","journal-title":"Autoimmun. Rev."},{"key":"2025030617482501200_r5","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.jhep.2010.01.037","article-title":"Treatment options for autoimmune hepatitis: a systematic review of randomized controlled trials","volume":"53","author":"Lamers","year":"2010","journal-title":"J. Hepatol."},{"key":"2025030617482501200_r6","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1111\/iep.12090","article-title":"Hepatitis mouse models: from acute-to-chronic autoimmune hepatitis","volume":"95","author":"Y\u00fcksel","year":"2014","journal-title":"Int. J. Exp. Pathol."},{"key":"2025030617482501200_r7","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1053\/jhep.2000.17701","article-title":"Murine concanavalin A-induced hepatitis is prevented by interleukin 12 (IL-12) antibody and exacerbated by exogenous IL-12 through an interferon-\u03b3-dependent mechanism","volume":"32","author":"Nicoletti","year":"2000","journal-title":"Hepatology"},{"key":"2025030617482501200_r8","first-page":"1693","article-title":"Role of interferon-gamma in interleukin 12-induced pathology in mice","volume":"147","author":"Car","year":"1995","journal-title":"Am. J. 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