{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T14:28:31Z","timestamp":1782743311934,"version":"3.54.5"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T00:00:00Z","timestamp":1685404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The use of noninvasive biomarkers may avoid the need for liver biopsy (LB) and could guide immunosuppression adjustment in liver transplantation (LT). The aims of this study were: to confirm the predictive and diagnostic capacity of plasmatic expression of miR-155-5p, miR-181a-5p, miR-122-5p and CXCL-10 for assessing T-cell mediated rejection (TCMR) risk; to develop a score based on a panel of noninvasive biomarkers to predict graft rejection risk and to validate this score in a separate cohort.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A prospective, observational study was conducted with a cohort of 79 patients followed during the first year after LT. Plasma samples were collected at predetermined time points for the analysis of miRNAs and the CXCL-10. Patients with LFTs abnormalities were submitted to a LB to rule out rejection, assessing previous and concurrent expression of the biomarkers to evaluate their predictive and diagnostic ability. Information from 86 patients included in a previous study was collected and used as a validation cohort.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twenty-four rejection episodes were diagnosed in 22 patients. Plasmatic CXCL-10 concentration and the expression of the three miRNAs were significantly elevated prior to and at the moment of the diagnosis of rejection. We developed a logistic model for rejection prediction and diagnosis, which included CXCL-10, miR-155-5p and miR-181a-5p. The area under the ROC curve (AUROC) for rejection prediction was 0.975 (79.6% sensitivity, 99.1% specificity, 90,7% PPV; 97.7% NPV; 97.1% correctly classified) and 0.99 for diagnosis (87.5% sensitivity, 99.5% specificity, 91.3% PPV; 99.3% NPV; 98.9% correctly classified). In the validation cohort (n=86; 14 rejections), the same cut-off points were used obtaining AUROCs for rejection prediction and diagnosis of 0.89 and 0.92 respectively. In patients with graft dysfunction in both cohorts the score could discriminate those with rejection regarding other causes with an AUROC of 0.98 (97.3% sensitivity, 94.1%specificity).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results suggest that the clinical implementation of the monitoring of this noninvasive plasmatic score may allow the prediction and diagnosis of rejection and identify patients with graft dysfunction due to rejection, helping with a more efficient guide for immunosuppressive therapy adjustment. This finding warrants the development of prospective biomarker-guided clinical trials.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1196882","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T11:02:05Z","timestamp":1685530925000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["A plasmatic score using a miRNA signature and CXCL-10 for accurate prediction and diagnosis of liver allograft rejection"],"prefix":"10.3389","volume":"14","author":[{"given":"Olga","family":"Mill\u00e1n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judit","family":"Julian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Lizana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiliam","family":"Fundora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Crespo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Colmenero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miquel","family":"Navasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merc\u00e8","family":"Brunet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1097\/FTD.0000000000000287","article-title":"Barcelona Consensus on biomarker-based immunosuppressive drugs management in solid organ transplantation","volume":"38","author":"Brunet","year":"2016","journal-title":"Ther Drug Monit"},{"key":"B2","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1097\/FTD.0000000000000640","article-title":"Therapeutic drug monitoring of tacrolimus-personalized therapy: second consensus report","volume":"41","author":"Brunet","year":"2019","journal-title":"Ther Drug Monit"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000003895","article-title":"Prediction of liver transplant rejection with a biologically relevant gene expression signature","volume":"106","author":"Levitsky","year":"2022","journal-title":"Transplantation"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/lt.26272","article-title":"Monitoring of donor-derived cell-free DNA by short tandem repeats: concentration of total cell-free DNA and fragment size for acute rejection risk assessment in liver transplantation","volume":"28","author":"Fern\u00e1ndez-Gal\u00e1n","year":"2022","journal-title":"Liver Transplant"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.15953","article-title":"Discovery and validation of a novel blood-based molecular biomarker of rejection following liver transplantation","volume":"20","author":"Levitsky","year":"2020","journal-title":"Am J Transplantation."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/lt.22438","article-title":"Hepatocyte-derived microRNAs as serum biomarkers of hepatic injury and rejection after liver transplantation","volume":"18","author":"Farid","year":"2012","journal-title":"Liver Transplantation."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28786","article-title":"An ectopically expressed serum miRNA signature is prognostic, diagnostic, and biologically related to liver allograft rejection LIVER BIOLOGY\/PATHOBIOLOGY","volume":"65","author":"Shaked","year":"2017","journal-title":"HEPATOLOGY"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0187336","article-title":"Multi-categorical deep learning neural network to classify retinal images: a pilot study employing small database","volume":"12","author":"Choi","year":"2017","journal-title":"PloS One"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.15959","article-title":"Development and validation of an optimized integrative model using urinary chemokines for noninvasive diagnosis of acute allograft rejection","volume":"20","author":"Tinel","year":"2020","journal-title":"Am J Transplantation."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0220052","article-title":"A urinary common rejection module (uCRM) score for non-invasive kidney transplant monitoring","volume":"14","author":"Sigdel","year":"2019","journal-title":"PloS One"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aba2501","article-title":"A urine score for noninvasive accurate diagnosis and prediction of kidney transplant rejection","volume":"12","author":"Yang","year":"2020","journal-title":"Sci Transl Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2016.07.035","article-title":"Acute rejection increases risk of graft failure and death in recent liver transplant recipients","volume":"15","author":"Levitsky","year":"2017","journal-title":"Clin Gastroenterol Hepatology."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1177\/0300060518785543","article-title":"Acute allograft rejection in liver transplant recipients: incidence, risk factors, treatment success, and impact on graft failure","volume":"46","author":"Dogan","year":"2018","journal-title":"J Int Med Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/flgastro-2018-101139","article-title":"Medical liver biopsy: background, indications, procedure and histopathology","volume":"11","author":"Boyd","year":"2020","journal-title":"Frontline Gastroenterol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.04.012","article-title":"Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients","volume":"69","author":"Londo\u00f1o","year":"2018","journal-title":"J Hepatol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2012.09.020","article-title":"Modulation of immune responses following solid organ transplantation by microRNA","volume":"93","author":"Sarma","year":"2012","journal-title":"Exp Mol Pathol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2010.03032.x","article-title":"MicroRNAs as immune regulators: implications for transplantation","volume":"10","author":"Harris","year":"2010","journal-title":"Am J Transplantation."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nri2252","article-title":"Micromanagement of the immune system by microRNAs","volume":"8","author":"Lodish","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"B19","article-title":"Circulating non-coding RNAs as potential diagnostic biomarkers in liver diseases","volume":"14","author":"Mokhtari","year":"","journal-title":"Gastroenterol Hepatol From Bed to Bench."},{"key":"B20","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1002\/hep.29833","article-title":"Expression of microRNA-155 in inflammatory cells modulates liver injury","volume":"68","author":"Blaya","year":"2018","journal-title":"Hepatology."},{"key":"B21","doi-asserted-by":"publisher","first-page":"714","DOI":"10.3892\/mmr.2021.12353","article-title":"Functional role of miR-155 in physiological and pathological processes of liver injury (Review)","volume":"24","author":"Feng","year":"2021","journal-title":"Mol Med Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00873","article-title":"Monitoring of miR-181a-5p and miR-155-5p plasmatic expression as prognostic biomarkers for acute and subclinical rejection in de novo adult liver transplant recipients","volume":"10","author":"Mill\u00e1n","year":"2019","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/lt.25842","article-title":"MicroRNAs 155-5p, 122-5p, and 181a-5p identify patients with graft dysfunction due to T cell\u2013mediated rejection after liver transplantation","volume":"26","author":"Ruiz","year":"2020","journal-title":"Liver Transplant"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/liv.12627","article-title":"Elevated miR-122 serum levels are an independent marker of liver injury in inflammatory diseases","volume":"35","author":"Roderburg","year":"2015","journal-title":"Liver Int"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2017.10.026","article-title":"MicroRNAs as biomarkers for liver injury: current knowledge, challenges and future prospects","volume":"110","author":"Lin","year":"2017","journal-title":"Food Chem Toxicology."},{"key":"B26","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1080\/1354750X.2016.1201538","article-title":"Bile: miRNA pattern and protein-based biomarkers may predict acute cellular rejection after liver transplantation","volume":"22","author":"Schmuck","year":"2017","journal-title":"Biomarkers"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2011.03680.x","article-title":"Urinary chemokines CXCL9 and CXCL10 are noninvasive markers of renal allograft rejection and BK viral infection","volume":"11","author":"Jackson","year":"2011","journal-title":"Am J Transplantation."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5000343","article-title":"Early post-transplant urinary IP-10 expression after kidney transplantation is predictive of short- and long-term graft function","volume":"69","author":"Matz","year":"2006","journal-title":"Kidney Int"},{"key":"B29","doi-asserted-by":"publisher","first-page":"108792","DOI":"10.1016\/j.clim.2021.108792","article-title":"Advantages of plasmatic CXCL-10 as a prognostic and diagnostic biomarker for the risk of rejection and subclinical rejection in kidney transplantation","volume":"229","author":"Mill\u00e1n","year":"2021","journal-title":"Clin Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13399","article-title":"Urinary miR-155-5p and CXCL10 as prognostic and predictive biomarkers of rejection, graft outcome and treatment response in kidney transplantation","volume":"83","author":"Mill\u00e1n","year":"2017","journal-title":"Br J Clin Pharmacol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.13677","article-title":"Early low urinary CXCL9 and CXCL10 might predict immunological quiescence in clinically and histologically stable kidney recipients","volume":"16","author":"Rabant","year":"2016","journal-title":"Am J Transplantation."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.14348\/molcells.2016.0130","article-title":"Combined detection of serum IL-10, IL-17, and CXCL10 predicts acute rejection following adult liver transplantation","volume":"39","author":"Kim","year":"2016","journal-title":"Mol Cells"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/lt.24164","article-title":"CD44 and CXCL9 serum protein levels predict the risk of clinically significant allograft rejection after liver transplantation","volume":"21","author":"Raschzok","year":"2015","journal-title":"Liver Transplant"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00663.x","article-title":"Noninvasive detection of renal allograft inflammation by measurements of mRNA for IP-10 and CXCR3 in urine","volume":"65","author":"Tatapudi","year":"2004","journal-title":"Kidney Int"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.13909","article-title":"Comprehensive update of the banff working group on liver allograft pathology: introduction of antibody-mediated rejection","volume":"16","author":"Demetris","year":"2016","journal-title":"Am J Transplantation."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1126\/science.1139253","article-title":"Requirement of bic\/microRNA-155 for normal immune function","volume":"316","author":"Rodriguez","year":"2007","journal-title":"Sci (1979)"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2018.0155","article-title":"MicroRNA-155: a master regulator of inflammation","volume":"39","author":"Mahesh","year":"2019","journal-title":"J Interferon Cytokine Res"},{"key":"B38","doi-asserted-by":"publisher","first-page":"109775","DOI":"10.1016\/j.intimp.2023.109775","article-title":"The role of miR-155 on liver diseases by modulating immunity, inflammation and tumorigenesis","volume":"116","author":"Xue","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.03.008","article-title":"miR-181a is an intrinsic modulator of T cell sensitivity and selection","volume":"129","author":"Li","year":"2007","journal-title":"Cell"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401587","article-title":"Mir-181a-1\/b-1 modulates tolerance through opposing activities in selection and peripheral T cell function","volume":"195","author":"Schaffert","year":"2015","journal-title":"J Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2020.05.018","article-title":"Circulating miR-181a-5p as a new biomarker for acute cellular rejection in heart transplantation","volume":"39","author":"Constanso-Conde","year":"2020","journal-title":"J Heart Lung Transplant"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903831","article-title":"CXC chemokine ligand (CXCL) 9 and CXCL10 are antagonistic costimulation molecules during the priming of alloreactive T cell effectors","volume":"184","author":"Rosenblum","year":"2010","journal-title":"J Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.10.1515","article-title":"Requirement of the chemokine receptor CXCR3 for acute allograft rejection","volume":"192","author":"Hancock","year":"2000","journal-title":"J Exp Med"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4161\/rna.18827","article-title":"Liver-specific microRNA-122: biogenesis and function","volume":"9","author":"Jopling","year":"2012","journal-title":"RNA Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1196882\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T11:02:19Z","timestamp":1685530939000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1196882\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,30]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2023.1196882"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1196882","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,30]]},"article-number":"1196882"}}