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Title: CD4+ T cells mediate the development of liver fibrosis in high fat diet-induced NAFLD in humanized mice
Authors: Her, Zhisheng
Tan, Joel Heng Loong
Lim, Yee-Siang
Tan, Sue Yee
Chan, Xue Ying
Tan, Wilson Wei Sheng
Liu, Min
Yong, Kylie Su Mei
Lai, Fritz
Ceccarello, Erica
Zheng, Zhiqiang
Fan, Yong
Chang, Kenneth Tou En
Sun, Lei
Chang, Shih Chieh
Chin, Chih-Liang
Lee, Guan Huei
Dan, Yock Young
Chan, Yun-Shen
Lim, Seng Gee
Chan, Jerry Kok Yen
Chandy, Kanianthara George
Chen, Qingfeng
Keywords: Science::Biological sciences
Issue Date: 2020
Source: Her, 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.2020.580968
Project: NRF-NRFF2017-03 
Journal: Frontiers in Immunology 
Abstract: Non-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.
ISSN: 1664-3224
DOI: 10.3389/fimmu.2020.580968
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
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.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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