{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T11:20:35Z","timestamp":1777116035245,"version":"3.51.4"},"reference-count":25,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,10,3]],"date-time":"2021-10-03T00:00:00Z","timestamp":1633219200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI19\/00883"],"award-info":[{"award-number":["PI19\/00883"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI16\/01748"],"award-info":[{"award-number":["PI16\/01748"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["P18\u2010RT\u20103364\u20102020"],"award-info":[{"award-number":["P18\u2010RT\u20103364\u20102020"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PT20\/000127"],"award-info":[{"award-number":["PT20\/000127"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:p>The identification of specific HLA risk alleles in drug\u2010induced liver injury (DILI) points toward an important role of the adaptive immune system in DILI development. In this study, we aimed to corroborate the role of an adaptive immune response in DILI through immunophenotyping of leukocyte populations and immune checkpoint expressions. Blood samples were collected from adjudicated DILI (<jats:italic>n<\/jats:italic>\u00a0=\u00a012), acute viral hepatitis (VH; <jats:italic>n<\/jats:italic>\u00a0=\u00a013), acute autoimmune hepatitis (AIH; <jats:italic>n<\/jats:italic>\u00a0=\u00a09), and acute liver injury of unknown etiology (<jats:italic>n<\/jats:italic>\u00a0=\u00a015) at day 1 (recognition), day 7, and day &gt;30. Blood samples from patients with nonalcoholic fatty liver disease (NAFLD; <jats:italic>n<\/jats:italic>\u00a0=\u00a020) and healthy liver controls (HLCs; <jats:italic>n<\/jats:italic>\u00a0=\u00a054) were extracted at one time point. Leukocyte populations and immune checkpoint expressions were determined based on cell surface receptors, except for CTLA\u20104 that was determined intracellularly, using flow cytometry. At recognition, DILI demonstrated significantly higher levels of activated helper T\u2010cell (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), activated cytotoxic T\u2010cells (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0003), Th1 (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0358), intracellular CTLA\u20104 level in helper T\u2010cells (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0192), and PD\u2010L1 presenting monocytes (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0452) than HLC. These levels approached those of HLC over time. No significant differences were found between DILI and VH. However, DILI presented higher level of activated helper T\u2010cells and CTLA\u20104 than NAFLD and lower PD\u2010L1 level than AIH. Our findings suggest that an adaptive immune response is involved in DILI in which activated CD4+ and CD8+ play an important role. Increased expression of negative immune checkpoints is likely the effect of peripheral tolerance regulation.<\/jats:p>","DOI":"10.1002\/cpt.2423","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T17:00:22Z","timestamp":1632157222000},"page":"1604-1612","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Lymphocyte Profile and Immune Checkpoint Expression in Drug\u2010Induced Liver Injury: An Immunophenotyping Study"],"prefix":"10.1111","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5861-9250","authenticated-orcid":false,"given":"Alejandro","family":"Cueto\u2010Sanchez","sequence":"first","affiliation":[{"name":"Servicio de Farmacolog\u00eda Cl\u00ednica and UGC Aparato Digestivo Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga\u2010IBIMA Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga M\u00e1laga Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Niu","sequence":"additional","affiliation":[{"name":"Servicio de Farmacolog\u00eda Cl\u00ednica and UGC Aparato Digestivo Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga\u2010IBIMA Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga M\u00e1laga Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Del Campo\u2010Herrera","sequence":"additional","affiliation":[{"name":"Servicio de Farmacolog\u00eda Cl\u00ednica and UGC Aparato Digestivo Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga\u2010IBIMA Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga M\u00e1laga Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Robles\u2010D\u00edaz","sequence":"additional","affiliation":[{"name":"Servicio de Farmacolog\u00eda Cl\u00ednica and UGC Aparato Digestivo Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga\u2010IBIMA Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga M\u00e1laga Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en el \u00c1rea Tem\u00e1tica de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Sanabria\u2010Cabrera","sequence":"additional","affiliation":[{"name":"Servicio de Farmacolog\u00eda Cl\u00ednica and UGC Aparato Digestivo Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga\u2010IBIMA Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga M\u00e1laga Spain"},{"name":"Platform ISCiii for Clinical Research and Clinical Trials UICEC\u2010IBIMA Malaga Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aida","family":"Ortega\u2010Alonso","sequence":"additional","affiliation":[{"name":"Servicio de Farmacolog\u00eda Cl\u00ednica and UGC Aparato Digestivo Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga\u2010IBIMA Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga M\u00e1laga Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en el \u00c1rea Tem\u00e1tica de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miren","family":"Garcia\u2010Cortes","sequence":"additional","affiliation":[{"name":"Servicio de Farmacolog\u00eda Cl\u00ednica and UGC Aparato Digestivo Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga\u2010IBIMA Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga M\u00e1laga Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en el \u00c1rea Tem\u00e1tica de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rocio","family":"Gonzalez\u2010Grande","sequence":"additional","affiliation":[{"name":"Servicio de Aparato Digestivo IBIMA, Hospital Universitario Regional de M\u00e1laga M\u00e1laga Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel","family":"Jimenez\u2010Perez","sequence":"additional","affiliation":[{"name":"Servicio de Aparato Digestivo IBIMA, Hospital Universitario Regional de M\u00e1laga M\u00e1laga Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco","family":"Ruiz\u2010Cabello","sequence":"additional","affiliation":[{"name":"Servicio de An\u00e1lisis Cl\u00ednicos e Inmunolog\u00eda UGC de Laboratorio Cl\u00ednico Hospital Universitario Virgen de las Nieves Granada Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1565-0757","authenticated-orcid":false,"given":"Ra\u00fal J.","family":"Andrade","sequence":"additional","affiliation":[{"name":"Servicio de Farmacolog\u00eda Cl\u00ednica and UGC Aparato Digestivo Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga\u2010IBIMA Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga M\u00e1laga Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en el \u00c1rea Tem\u00e1tica de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9586-4896","authenticated-orcid":false,"given":"M. Isabel","family":"Lucena","sequence":"additional","affiliation":[{"name":"Servicio de Farmacolog\u00eda Cl\u00ednica and UGC Aparato Digestivo Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga\u2010IBIMA Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga M\u00e1laga Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en el \u00c1rea Tem\u00e1tica de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) Madrid Spain"},{"name":"Platform ISCiii for Clinical Research and Clinical Trials UICEC\u2010IBIMA Malaga Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0796-9610","authenticated-orcid":false,"given":"Camilla","family":"Stephens","sequence":"additional","affiliation":[{"name":"Servicio de Farmacolog\u00eda Cl\u00ednica and UGC Aparato Digestivo Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga\u2010IBIMA Hospital Universitario Virgen de la Victoria Universidad de M\u00e1laga M\u00e1laga Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en el \u00c1rea Tem\u00e1tica de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,10,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.04.016"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22062954"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2019.08.003"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v16.i48.6046"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.12988"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-018-5072-x"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13198"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0000000000000336"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00304"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00662.x"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.10.008"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1159\/000282062"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.58"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2003.02109.x"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.11-0523"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.157.2.461"},{"key":"e_1_2_9_18_1","first-page":"1603 (2017)","article-title":"Induction of a regulatory phenotype in CD3+ CD4+ HLA\u2010DR+ T cells after allogeneic mixed lymphocyte culture; indications of both contact\u2010dependent and \u2013independent activation","volume":"18","author":"Revenfeld A.L.S.","journal-title":"Int. J. Mol. Sci."},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.8.4622"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26077"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27912"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18071517"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4906(01)01888-9"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.304329"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2018.08.020"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.9.5062"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2423","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.2423","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2423","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T13:30:42Z","timestamp":1699363842000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.2423"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,3]]},"references-count":25,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10.1002\/cpt.2423"],"URL":"https:\/\/doi.org\/10.1002\/cpt.2423","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,3]]},"assertion":[{"value":"2021-06-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}