{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T08:05:39Z","timestamp":1784621139861,"version":"3.55.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2017,3,27]],"date-time":"2017-03-27T00:00:00Z","timestamp":1490572800000},"content-version":"vor","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":["G0902288"],"award-info":[{"award-number":["G0902288"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,6,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4+CD25\u2013 cells, isolated from the peripheral blood of treatment-naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)-\u03b3, interleukin (IL)-17 and tumour necrosis factor (TNF)-\u03b1 by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death-1 (PD-1), T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) and cytotoxic T lymphocyte antigen-4 (CTLA-4) increase over 96-h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN-\u03b3 and PD-1 expression in AIH, where control over CD4+CD25\u2013 cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4+CD25\u2013 cells more susceptible to Treg control. Collectively, our data indicate that in treatment-naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD-1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs.<\/jats:p>","DOI":"10.1111\/cei.12956","type":"journal-article","created":{"date-parts":[[2017,3,3]],"date-time":"2017-03-03T23:42:46Z","timestamp":1488584566000},"page":"71-82","source":"Crossref","is-referenced-by-count":22,"title":["Immunosuppressive drugs affect interferon (IFN)-\u03b3 and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis"],"prefix":"10.1093","volume":"189","author":[{"given":"C R","family":"Grant","sequence":"first","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B S","family":"Holder","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK"},{"name":"Department of Paediatrics, Imperial College, London"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Liberal","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK"},{"name":"Gastroenterology Department, Centro Hospitalar S\u00e3o Jo\u00e3o, Faculty of Medicine of the University of Porto, Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M A","family":"Heneghan","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Mieli-Vergani","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK"},{"name":"MowatLabs Paediatric Liver, GI and Nutrition Centre, King's College London, Faculty of Life Sciences and Medicine, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Vergani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4510-1249","authenticated-orcid":false,"given":"M S","family":"Longhi","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Faculty of Life Sciences and Medicine, London, UK"},{"name":"Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,3,27]]},"reference":[{"key":"2021120808104213300_cei12956-bib-0001","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/hep.22322","article-title":"Simplified criteria for the diagnosis of autoimmune hepatitis","volume":"48","author":"Hennes","year":"2008","journal-title":"Hepatology"},{"key":"2021120808104213300_cei12956-bib-0002","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jaut.2012.11.002","article-title":"Autoimmune hepatitis: a comprehensive review","volume":"41","author":"Liberal","year":"2013","journal-title":"J Autoimmun"},{"key":"2021120808104213300_cei12956-bib-0003","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.4049\/jimmunol.159.3.1418","article-title":"Suppression of concanavalin A-induced hepatitis in IFN-gamma(\u2013\/\u2013) mice, but not in TNF-alpha(\u2013\/\u2013) mice: role for IFN-gamma in activating apoptosis of hepatocytes","volume":"159","author":"Tagawa","year":"1997","journal-title":"J Immunol"},{"key":"2021120808104213300_cei12956-bib-0004","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1053\/gast.1996.v111.pm8690213","article-title":"Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A","volume":"111","author":"Kusters","year":"1996","journal-title":"Gastroenterology"},{"key":"2021120808104213300_cei12956-bib-0005","first-page":"1608","article-title":"Critical involvement of interferon gamma in the pathogenesis of T-cell activation-associated hepatitis and regulatory mechanisms of interleukin-6 for the manifestations of hepatitis","volume":"23","author":"Mizuhara","year":"1996","journal-title":"Hepatology"},{"key":"2021120808104213300_cei12956-bib-0006","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-gamma-dependent mechanism","volume":"32","author":"Nicoletti","year":"2000","journal-title":"Hepatology"},{"key":"2021120808104213300_cei12956-bib-0007","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1053\/j.gastro.2005.12.020","article-title":"Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2","volume":"130","author":"Ma","year":"2006","journal-title":"Gastroenterology"},{"key":"2021120808104213300_cei12956-bib-0008","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1002\/hep.25682","article-title":"The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9\/tim-3 pathway","volume":"56","author":"Liberal","year":"2012","journal-title":"Hepatology"},{"key":"2021120808104213300_cei12956-bib-0009","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/hep.22914","article-title":"Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells","volume":"50","author":"Longhi","year":"2009","journal-title":"Hepatology"},{"key":"2021120808104213300_cei12956-bib-0010","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1053\/j.gastro.2009.08.004","article-title":"Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating T helper 1 cytokine and interleukin-17 production","volume":"137","author":"Lafdil","year":"2009","journal-title":"Gastroenterology"},{"key":"2021120808104213300_cei12956-bib-0011","doi-asserted-by":"crossref","first-page":"7473","DOI":"10.4049\/jimmunol.181.11.7473","article-title":"Requirement of IL-17RA in Con A induced hepatitis and negative regulation of IL-17 production in mouse T cells","volume":"181","author":"Nagata","year":"2008","journal-title":"J Immunol"},{"key":"2021120808104213300_cei12956-bib-0012","doi-asserted-by":"crossref","first-page":"e18909","DOI":"10.1371\/journal.pone.0018909","article-title":"Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression","volume":"6","author":"Zhao","year":"2011","journal-title":"PLOS ONE"},{"key":"2021120808104213300_cei12956-bib-0013","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.dld.2014.02.003","article-title":"The association between cytotoxic T lymphocyte associated antigen-4, Fas, tumour necrosis factor-alpha gene polymorphisms and autoimmune hepatitis: a meta-analysis","volume":"46","author":"Qin","year":"2014","journal-title":"Dig Liver Dis"},{"key":"2021120808104213300_cei12956-bib-0014","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/s12041-013-0272-9","article-title":"Tumour necrosis factor alpha (TNF-alpha) genetic polymorphisms and the risk of autoimmune liver disease: a meta-analysis","volume":"92","author":"Li","year":"2013","journal-title":"J Genet"},{"key":"2021120808104213300_cei12956-bib-0015","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1002\/hep.510300412","article-title":"Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis","volume":"30","author":"Cookson","year":"1999","journal-title":"Hepatology"},{"key":"2021120808104213300_cei12956-bib-0016","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/S0016-5085(99)70458-0","article-title":"Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis","volume":"117","author":"Czaja","year":"1999","journal-title":"Gastroenterology"},{"key":"2021120808104213300_cei12956-bib-0017","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.jaut.2016.05.005","article-title":"CD39 mediated regulation of Th17-cell effector function is impaired in juvenile autoimmune liver disease","volume":"72","author":"Liberal","year":"2016","journal-title":"J Autoimmun"},{"key":"2021120808104213300_cei12956-bib-0018","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/ni.1817","article-title":"Mechanisms maintaining peripheral tolerance","volume":"11","author":"Mueller","year":"2010","journal-title":"Nat Immunol"},{"key":"2021120808104213300_cei12956-bib-0019","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jhep.2004.03.008","article-title":"Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease","volume":"41","author":"Longhi","year":"2004","journal-title":"J Hepatol"},{"key":"2021120808104213300_cei12956-bib-0020","doi-asserted-by":"crossref","first-page":"4484","DOI":"10.4049\/jimmunol.176.7.4484","article-title":"Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis","volume":"176","author":"Longhi","year":"2006","journal-title":"J Immunol"},{"key":"2021120808104213300_cei12956-bib-0021","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1002\/hep.23792","article-title":"A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis","volume":"52","author":"Ferri","year":"2010","journal-title":"Hepatology"},{"key":"2021120808104213300_cei12956-bib-0022","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jaut.2005.05.001","article-title":"Effect of CD4+ CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis","volume":"25","author":"Longhi","year":"2005","journal-title":"J Autoimmun"},{"key":"2021120808104213300_cei12956-bib-0023","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/hep.26583","article-title":"Dysfunctional CD39(POS) regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis","volume":"59","author":"Grant","year":"2014","journal-title":"Hepatology"},{"key":"2021120808104213300_cei12956-bib-0024","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/hep.27884","article-title":"In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression","volume":"62","author":"Liberal","year":"2015","journal-title":"Hepatology"},{"key":"2021120808104213300_cei12956-bib-0025","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1136\/thorax.55.7.603","article-title":"Molecular mechanisms of glucocorticoid action: what is important?","volume":"55","author":"Newton","year":"2000","journal-title":"Thorax"},{"key":"2021120808104213300_cei12956-bib-0026","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1172\/JCI200318384","article-title":"Azathioprine: old drug, new actions","volume":"111","author":"Maltzman","year":"2003","journal-title":"J Clin Invest"},{"key":"2021120808104213300_cei12956-bib-0027","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.jhep.2009.02.024","article-title":"Mycophenolate mofetil as rescue treatment for autoimmune liver disease in children: a 5-year follow-up","volume":"51","author":"Aw","year":"2009","journal-title":"J Hepatol"},{"key":"2021120808104213300_cei12956-bib-0028","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1155\/2004\/504591","article-title":"Mycophenolate mofetil for the treatment of autoimmune hepatitis in patients refractory to standard therapy","volume":"18","author":"Devlin","year":"2004","journal-title":"Can J Gastroenterol"},{"key":"2021120808104213300_cei12956-bib-0029","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.cgh.2008.04.006","article-title":"A single center review of the use of mycophenolate mofetil in the treatment of autoimmune hepatitis","volume":"6","author":"Hlivko","year":"2008","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2021120808104213300_cei12956-bib-0030","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.cgh.2007.02.030","article-title":"Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy","volume":"5","author":"Inductivo-Yu","year":"2007","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2021120808104213300_cei12956-bib-0031","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/S0168-8278(00)80271-8","article-title":"Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine","volume":"33","author":"Richardson","year":"2000","journal-title":"J Hepatol"},{"key":"2021120808104213300_cei12956-bib-0032","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/S0168-8278(99)80065-8","article-title":"Short-term cyclosporine induces a remission of autoimmune hepatitis in children","volume":"30","author":"Alvarez","year":"1999","journal-title":"J Hepatol"},{"key":"2021120808104213300_cei12956-bib-0033","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1097\/01.mpg.0000235975.75120.38","article-title":"Follow-up of children with autoimmune hepatitis treated with cyclosporine","volume":"43","author":"Cuarterolo","year":"2006","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"2021120808104213300_cei12956-bib-0034","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1023\/A:1010683817344","article-title":"Cyclosporin A is a promising alternative to corticosteroids in autoimmune hepatitis","volume":"46","author":"Malekzadeh","year":"2001","journal-title":"Dig Dis Sci"},{"key":"2021120808104213300_cei12956-bib-0035","doi-asserted-by":"crossref","first-page":"3232","DOI":"10.3748\/wjg.v13.i23.3232","article-title":"Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis","volume":"13","author":"Larsen","year":"2007","journal-title":"World J Gastroenterol"},{"key":"2021120808104213300_cei12956-bib-0036","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S0009-9120(98)00045-9","article-title":"Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression","volume":"31","author":"Sehgal","year":"1998","journal-title":"Clin Biochem"},{"key":"2021120808104213300_cei12956-bib-0037","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/978-1-61779-430-8_17","article-title":"Expanding human T regulatory cells with the mTOR-inhibitor rapamycin","volume":"821","author":"Battaglia","year":"2012","journal-title":"Methods Mol Biol"},{"key":"2021120808104213300_cei12956-bib-0038","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1053\/jhep.2001.22131","article-title":"Autoimmune hepatitis\/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study","volume":"33","author":"Gregorio","year":"2001","journal-title":"Hepatology"},{"key":"2021120808104213300_cei12956-bib-0039","first-page":"555A","article-title":"Genetically determined abnormality of the PD-1\/PD-LS pathway may predispose to autoimmune liver disease","volume":"46","author":"Wang","year":"2007","journal-title":"Hepatology"},{"key":"2021120808104213300_cei12956-bib-0040","doi-asserted-by":"crossref","first-page":"207","DOI":"10.3389\/fimmu.2013.00207","article-title":"Liver FOXP3 and PD1\/PDL1 expression is down-regulated in chronic HBV hepatitis on maintained remission related to the degree of inflammation","volume":"4","author":"Germanidis","year":"2013","journal-title":"Front Immunol"},{"key":"2021120808104213300_cei12956-bib-0041","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nm1564","article-title":"Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation","volume":"13","author":"Korn","year":"2007","journal-title":"Nat Med"},{"key":"2021120808104213300_cei12956-bib-0042","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.trim.2007.01.002","article-title":"The effect of immunosuppressive drug rapamycin on regulatory CD4+CD25+Foxp3+T cells in mice","volume":"17","author":"Qu","year":"2007","journal-title":"Transpl Immunol"},{"key":"2021120808104213300_cei12956-bib-0043","doi-asserted-by":"crossref","first-page":"320","DOI":"10.4049\/jimmunol.178.1.320","article-title":"Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin","volume":"178","author":"Strauss","year":"2007","journal-title":"J Immunol"},{"key":"2021120808104213300_cei12956-bib-0044","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jaut.2014.02.001","article-title":"Retinoic acid stabilizes antigen-specific regulatory T-cell function in autoimmune hepatitis type 2","volume":"53","author":"Holder","year":"2014","journal-title":"J Autoimmun"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcei.12956","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/189\/1\/71\/41643688\/cei12956.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/189\/1\/71\/41643688\/cei12956.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T13:22:05Z","timestamp":1692710525000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/189\/1\/71\/6412424"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,27]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,3,27]]},"published-print":{"date-parts":[[2017,6,6]]}},"URL":"https:\/\/doi.org\/10.1111\/cei.12956","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"value":"0009-9104","type":"print"},{"value":"1365-2249","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,7]]},"published":{"date-parts":[[2017,3,27]]}}}