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dc.contributor.authorHer, Zhishengen_US
dc.contributor.authorTan, Joel Heng Loongen_US
dc.contributor.authorLim, Yee-Siangen_US
dc.contributor.authorTan, Sue Yeeen_US
dc.contributor.authorChan, Xue Yingen_US
dc.contributor.authorTan, Wilson Wei Shengen_US
dc.contributor.authorLiu, Minen_US
dc.contributor.authorYong, Kylie Su Meien_US
dc.contributor.authorLai, Fritzen_US
dc.contributor.authorCeccarello, Ericaen_US
dc.contributor.authorZheng, Zhiqiangen_US
dc.contributor.authorFan, Yongen_US
dc.contributor.authorChang, Kenneth Tou Enen_US
dc.contributor.authorSun, Leien_US
dc.contributor.authorChang, Shih Chiehen_US
dc.contributor.authorChin, Chih-Liangen_US
dc.contributor.authorLee, Guan Hueien_US
dc.contributor.authorDan, Yock Youngen_US
dc.contributor.authorChan, Yun-Shenen_US
dc.contributor.authorLim, Seng Geeen_US
dc.contributor.authorChan, Jerry Kok Yenen_US
dc.contributor.authorChandy, Kanianthara Georgeen_US
dc.contributor.authorChen, Qingfengen_US
dc.identifier.citationHer, Z., Tan, J. H. L., Lim, Y.-S., Tan, S. Y., Chan, X. Y., Tan, W. W. S., . . . Chen, Q. (2020). CD4+ T cells mediate the development of liver fibrosis in high fat diet-induced NAFLD in humanized mice. Frontiers in Immunology, 11, 580968-. doi:10.3389/fimmu.2020.580968en_US
dc.description.abstractNon-alcoholic fatty liver disease (NAFLD) has been on a global rise. While animal models have rendered valuable insights to the pathogenesis of NAFLD, discrepancy with patient data still exists. Since non-alcoholic steatohepatitis (NASH) involves chronic inflammation, and CD4+ T cell infiltration of the liver is characteristic of NASH patients, we established and characterized a humanized mouse model to identify human-specific immune response(s) associated with NAFLD progression. Immunodeficient mice engrafted with human immune cells (HIL mice) were fed with high fat and high calorie (HFHC) or chow diet for 20 weeks. Liver histology and immune profile of HIL mice were analyzed and compared with patient data. HIL mice on HFHC diet developed steatosis, inflammation and fibrosis of the liver. Human CD4+ central and effector memory T cells increased within the liver and in the peripheral blood of our HIL mice, accompanied by marked up-regulation of pro-inflammatory cytokines (IL-17A and IFNγ). In vivo depletion of human CD4+ T cells in HIL mice reduced liver inflammation and fibrosis, but not steatosis. Our results highlight CD4+ memory T cell subsets as important drivers of NAFLD progression from steatosis to fibrosis and provides a humanized mouse model for pre-clinical evaluation of potential therapeutics.en_US
dc.description.sponsorshipAgency for Science, Technology and Research (A*STAR)en_US
dc.description.sponsorshipNational Medical Research Council (NMRC)en_US
dc.description.sponsorshipNational Research Foundation (NRF)en_US
dc.relation.ispartofFrontiers in Immunologyen_US
dc.rights© 2020 Her, Tan, Lim, Tan, Chan, Tan, Liu, Yong, Lai, Ceccarello, Zheng, Fan, Chang, Sun, Chang, Chin, Lee, Dan, Chan, Lim, Chan, Chandy and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en_US
dc.subjectScience::Biological sciencesen_US
dc.titleCD4+ T cells mediate the development of liver fibrosis in high fat diet-induced NAFLD in humanized miceen_US
dc.typeJournal Articleen
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.description.versionPublished versionen_US
dc.subject.keywordsHumanized Mouse Modelen_US
dc.description.acknowledgementThis study was supported by the National Research Foundation Singapore Fellowship (NRF-NRFF2017-03), NRF-ISF joint grant (NRF2019-NRF-ISF003-3127), Ensemble of Multi-Disciplinary Systems and Integrated Omics for NAFLD (EMULSION) diagnostic and therapeutic discovery (H18/01/a0/017), Agency for Science, Technology and Research (A∗STAR), Gilead Sciences International Research Scholars Program in Liver Disease (to QC), National Natural Science Foundation of China (81970520), and National Medical Research Council – Clinician Scientist – Individual Research Grant (NMRC/CIRG/1427/2015).en_US
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