{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T20:02:25Z","timestamp":1791576145043,"version":"4.3.4"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":973,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,1]]},"abstract":"<jats:sec>\n            <jats:title>Abstract<\/jats:title>\n            <jats:p>Autoimmune hepatitis (AIH) is characterized by a loss of immunological tolerance to hepatocytes. Patients respond well to immunosuppression but progression to endstage liver disease occurs in 10%-20% of cases, leading to liver transplantation. Using a murine model of type 2 AIH, we identified susceptibility factors for autoimmune hepatitis and attempted to restore immunological tolerance to liver autoantigens. An increased ectopic expression of a liver autoantigen (FTCD) in the thymus leading to reduced numbers of circulating autoreactive T cells was sufficient to prevent development of AIH in mice. However, in the presence of a reduced central tolerance to FTCD, a strong regulatory T-cell response was able to inhibit proliferation of liver-specific autoreactive T cells and prevent AIH. Development of a severe AIH stemmed from reduced numbers of functional regulatory T cell (Tregs) leading to an increased proliferation of FTCD-specific autoreactive T and B cells. Adoptive transfer of <jats:italic toggle=\"yes\">ex vivo<\/jats:italic> expanded CXCR3<jats:sup>+<\/jats:sup> Tregs in mice with AIH efficiently targeted the inflamed liver, restored peripheral tolerance to FTCD, and induced remission of AIH. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Peripheral tolerance to liver autoantigens in AIH is paramount. Autologous infusion of <jats:italic toggle=\"yes\">ex vivo<\/jats:italic> expanded CXCR3<jats:sup>+<\/jats:sup> Tregs in AIH patients could be an effective therapeutic approach to restore peripheral tolerance and induce remission of AIH. (Hepatology 2013)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.26023","type":"journal-article","created":{"date-parts":[[2012,8,22]],"date-time":"2012-08-22T08:27:45Z","timestamp":1345624065000},"page":"217-227","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":100,"title":["Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance"],"prefix":"10.1097","volume":"57","author":[{"given":"Pascal","family":"Lapierre","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathie","family":"B\u00e9land","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R2-24-20241201","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1016\/j.jhep.2004.03.008","article-title":"Impairment of CD4 ()CD25 () regulatory Tcells in autoimmune liver disease.","volume":"41","author":"Longhi","year":"2004","journal-title":"J Hepatol"},{"key":"R3-24-20241201","doi-asserted-by":"crossref","first-page":"6371","DOI":"10.1016\/j.jaut.2005.05.001","article-title":"Effect of CD4 CD25 regulatory Tcells on CD8 Tcell function in patients with autoimmune hepatitis.","volume":"25","author":"Longhi","year":"2005","journal-title":"J Autoimmun"},{"key":"R4-24-20241201","doi-asserted-by":"crossref","first-page":"44844491","DOI":"10.4049\/jimmunol.176.7.4484","article-title":"Functional study of CD4CD25 regulatory T cells in health and autoimmune hepatitis.","volume":"176","author":"Longhi","year":"2006","journal-title":"J Immunol"},{"key":"R5-24-20241201","doi-asserted-by":"crossref","first-page":"581591","DOI":"10.1002\/hep.22071","article-title":"Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis.","volume":"47","author":"Longhi","year":"2008","journal-title":"HEPATOLOGY"},{"key":"R6-24-20241201","doi-asserted-by":"crossref","first-page":"536547","DOI":"10.1002\/hep.24039","article-title":"Autoantigenspecific regulatory T cells, a potential tool for immunetolerance reconstitution in type2 autoimmune hepatitis.","volume":"53","author":"Longhi","year":"2011","journal-title":"HEPATOLOGY"},{"key":"R7-24-20241201","doi-asserted-by":"crossref","first-page":"385388","DOI":"10.1002\/hep.24153","article-title":"Autoimmune hepatitis and antigenspecific T regulatory cells: when can we send in the regulators?","volume":"53","author":"Vierling","year":"2011","journal-title":"HEPATOLOGY"},{"key":"R8-24-20241201","first-page":"48894896","article-title":"DNA vaccination breaks tolerance for a neoself antigen in liver: a transgenic murine model of autoimmune hepatitis.","volume":"169","author":"DjilaliSaiah","year":"2002","journal-title":"J Immunol"},{"key":"R9-24-20241201","doi-asserted-by":"crossref","first-page":"8289","DOI":"10.1016\/j.jaut.2005.11.001","article-title":"Type 2 autoimmune hepatitis murine model: the influence of genetic background in disease development.","volume":"26","author":"Lapierre","year":"2006","journal-title":"J Autoimmun"},{"key":"R10-24-20241201","doi-asserted-by":"crossref","first-page":"17891798","DOI":"10.1002\/hep.23536","article-title":"Forkhead box p3 regulatory T cell underlies male resistance to experimental type 2 autoimmune hepatitis.","volume":"51","author":"Lapierre","year":"2010","journal-title":"HEPATOLOGY"},{"key":"R11-24-20241201","doi-asserted-by":"crossref","first-page":"10661074","DOI":"10.1002\/hep.20109","article-title":"A murine model of type 2 autoimmune hepatitis: xenoimmunization with human antigens.","volume":"39","author":"Lapierre","year":"2004","journal-title":"HEPATOLOGY"},{"key":"R12-24-20241201","doi-asserted-by":"crossref","first-page":"607615","DOI":"10.1016\/0896-8411(91)90180-K","article-title":"Identification of the main epitope on human cytochrome P450 IID6 recognized by antiliver kidney microsome antibody.","volume":"4","author":"Gueguen","year":"1991","journal-title":"J Autoimmun"},{"key":"R13-24-20241201","doi-asserted-by":"crossref","first-page":"11051111","DOI":"10.1002\/eji.1830230519","article-title":"Identification and analysis of cytochrome P450IID6 antigenic sites recognized by antiliverkidney microsome type1 antibodies (LKM1).","volume":"23","author":"Yamamoto","year":"1993","journal-title":"Eur J Immunol"},{"key":"R14-24-20241201","doi-asserted-by":"crossref","first-page":"10661072","DOI":"10.1172\/JCI113949","article-title":"Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1.","volume":"83","author":"Manns","year":"1989","journal-title":"J Clin Invest"},{"key":"R15-24-20241201","doi-asserted-by":"crossref","first-page":"643649","DOI":"10.1016\/S0016-5085(99)70186-1","article-title":"Formiminotransferase cyclodeaminase is an organspecific autoantigen recognized by sera of patients with autoimmune hepatitis.","volume":"116","author":"Lapierre","year":"1999","journal-title":"Gastroenterology"},{"key":"R16-24-20241201","doi-asserted-by":"crossref","first-page":"289292","DOI":"10.1038\/ng0397-289","article-title":"Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus.","volume":"15","author":"Vafiadis","year":"1997","journal-title":"Nat Genet"},{"key":"R17-24-20241201","doi-asserted-by":"crossref","first-page":"13831390","DOI":"10.2337\/diabetes.51.5.1383","article-title":"Insulin expression levels in the thymus modulate insulinspecific autoreactive Tcell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes.","volume":"51","author":"Chentoufi","year":"2002","journal-title":"Diabetes"},{"key":"R18-24-20241201","doi-asserted-by":"crossref","first-page":"293297","DOI":"10.1038\/ng0397-293","article-title":"The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTRIDDM2 susceptibility locus for type 1 diabetes.","volume":"15","author":"Pugliese","year":"1997","journal-title":"Nat Genet"},{"key":"R20-24-20241201","doi-asserted-by":"crossref","first-page":"10251034","DOI":"10.3748\/wjg.15.1025","article-title":"Influence of genes, sex, age and environment on the onset of autoimmune hepatitis.","volume":"15","author":"Beland","year":"2009","journal-title":"World J Gastroenterol"},{"key":"R21-24-20241201","doi-asserted-by":"crossref","first-page":"721726","DOI":"10.1136\/gut.42.5.721","article-title":"Liverkidney microsomal antibody type 1 and liver cytosol antibody type 1 concentrations in type 2 autoimmune hepatitis.","volume":"42","author":"Muratori","year":"1998","journal-title":"Gut"},{"key":"R22-24-20241201","doi-asserted-by":"crossref","first-page":"904909","DOI":"10.1016\/j.jhep.2004.02.023","article-title":"Linkage disequilibrium between HLA class II region and autoimmune hepatitis in pediatric patients.","volume":"40","author":"DjilaliSaiah","year":"2004","journal-title":"J Hepatol"},{"key":"R23-24-20241201","doi-asserted-by":"crossref","first-page":"10471052","DOI":"10.1053\/jhep.2001.24031","article-title":"Autoimmune regulator AIRE: evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1.","volume":"33","author":"Vogel","year":"2001","journal-title":"HEPATOLOGY"},{"key":"R24-24-20241201","doi-asserted-by":"crossref","first-page":"971979","DOI":"10.1084\/jem.20031579","article-title":"Loss of functional suppression by CD4CD25 regulatory T cells in patients with multiple sclerosis.","volume":"199","author":"Viglietta","year":"2004","journal-title":"J Exp Med"},{"key":"R25-24-20241201","doi-asserted-by":"crossref","first-page":"273276","DOI":"10.1016\/S0896-8411(03)00121-5","article-title":"Quantification of regulatory T cells in patients with systemic lupus erythematosus.","volume":"21","author":"Crispin","year":"2003","journal-title":"J Autoimmun"},{"key":"R26-24-20241201","doi-asserted-by":"crossref","first-page":"31053117","DOI":"10.1084\/jem.20081359","article-title":"Antigenspecific peripheral shaping of the natural regulatory T cell population.","volume":"205","author":"Lathrop","year":"2008","journal-title":"J Exp Med"},{"key":"R27-24-20241201","doi-asserted-by":"crossref","first-page":"559570","DOI":"10.1016\/j.immuni.2008.02.019","article-title":"Interleukin23 restrains regulatory T cell activity to drive T celldependent colitis.","volume":"28","author":"Izcue","year":"2008","journal-title":"Immunity"},{"key":"R28-24-20241201","doi-asserted-by":"crossref","first-page":"595602","DOI":"10.1038\/ni.1731","article-title":"The transcription factor Tbet controls regulatory T cell homeostasis and function during type 1 inflammation.","volume":"10","author":"Koch","year":"2009","journal-title":"Nat Immunol"},{"key":"R29-24-20241201","doi-asserted-by":"crossref","first-page":"28862898","DOI":"10.4049\/jimmunol.0901216","article-title":"Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver.","volume":"184","author":"Oo","year":"2010","journal-title":"J Immunol"},{"key":"R30-24-20241201","doi-asserted-by":"crossref","first-page":"52845293","DOI":"10.4049\/jimmunol.1003750","article-title":"CXCR3 deficiency exacerbates liver disease and abrogates tolerance in a mouse model of immunemediated hepatitis.","volume":"186","author":"Erhardt","year":"2011","journal-title":"J Immunol"},{"key":"R31-24-20241201","doi-asserted-by":"crossref","first-page":"27742786","DOI":"10.4049\/jimmunol.179.5.2774","article-title":"CXCR3 signaling reduces the severity of experimental autoimmune encephalomyelitis by controlling the parenchymal distribution of effector and regulatory T cells in the central nervous system.","volume":"179","author":"Muller","year":"2007","journal-title":"J Immunol"},{"key":"R32-24-20241201","doi-asserted-by":"crossref","first-page":"490500","DOI":"10.1038\/nri2785","article-title":"FOXP3 regulatory T cells in the human immune system.","volume":"10","author":"Sakaguchi","year":"2010","journal-title":"Nat Rev Immunol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.26023","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201301000-00024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T14:02:42Z","timestamp":1733061762000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201301000-00024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,1]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.26023","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2013,1]]}}}