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CD14+CD15-HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure

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Title: CD14+CD15-HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure
Authors: Bernsmeier, C
Triantafyllou, E
Brenig, R
Lebosse, F
Singanayagam, A
Patel, V
Pop, O
Khamri, W
Nathwani, R
Tidswell, R
Weston, C
Adams, D
Thursz, M
Wendon, J
Antoniades, C
Item Type: Journal Article
Abstract: Objective Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR− myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses. Design Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15−CD11b+HLA-DR− cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques. Results Circulating CD14+CD15−CD11b+HLA-DR− M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo. Conclusion Immunosuppressive CD14+HLA-DR− M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.
Issue Date: 7-Jun-2017
Date of Acceptance: 27-Apr-2017
URI: http://hdl.handle.net/10044/1/48341
DOI: https://dx.doi.org/10.1136/gutjnl-2017-314184
ISSN: 1468-3288
Publisher: BMJ Publishing Group
Start Page: 1155
End Page: 1167
Journal / Book Title: Gut
Volume: 67
Copyright Statement: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
Rosetrees Trust
Medical Research Council (MRC)
Rosetrees Trust
Wellcome Trust
Stoneygate Trust
Funder's Grant Number: RDA15 79560
JS16/M115-F1
MR/K010514/1
N/A
107303/Z/15/Z
n/a
Keywords: ACLF
ALF
MDSC
bacterial infection
cirrhosis
immune suppression
1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
Gastroenterology & Hepatology
Publication Status: Published
Appears in Collections:Division of Surgery
Faculty of Medicine



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