Bernsmeier, C;
Triantafyllou, E;
Brenig, R;
Lebosse, FJ;
Singanayagam, A;
Patel, VC;
Pop, OT;
Khamri, W;
Nathwani, R;
Tidswell, R;
et al.
Bernsmeier, C; Triantafyllou, E; Brenig, R; Lebosse, FJ; Singanayagam, A; Patel, VC; Pop, OT; Khamri, W; Nathwani, R; Tidswell, R; Weston, CJ; Adams, DH; Thursz, MR; Wendon, JA; Antoniades, CG
(2018)
CD14+ CD15- HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure.
Gut, 67 (6).
pp. 1155-1167.
ISSN 1468-3288
https://doi.org/10.1136/gutjnl-2017-314184
SGUL Authors: Singanayagam, Arjuna
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.
Item Type: |
Article
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Additional Information: |
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. 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/ |
Keywords: |
ACLF, ALF, MDSC, bacterial infection, cirrhosis, immune suppression, Acute-On-Chronic Liver Failure, Adult, Anti-Infective Agents, Cytokines, Flow Cytometry, Fucosyltransferases, HLA-DR Antigens, Humans, Immune Tolerance, Immunophenotyping, Lewis X Antigen, Lipopolysaccharide Receptors, Lymphocyte Activation, Middle Aged, Myeloid-Derived Suppressor Cells, Phagocytosis, Polymerase Chain Reaction, Prognosis, Humans, Fucosyltransferases, HLA-DR Antigens, Cytokines, Anti-Infective Agents, Prognosis, Flow Cytometry, Polymerase Chain Reaction, Immunophenotyping, Lymphocyte Activation, Phagocytosis, Immune Tolerance, Adult, Middle Aged, Acute-On-Chronic Liver Failure, Myeloid-Derived Suppressor Cells, Lewis X Antigen, Lipopolysaccharide Receptors, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology |
SGUL Research Institute / Research Centre: |
Academic Structure > Infection and Immunity Research Institute (INII) |
Journal or Publication Title: |
Gut |
ISSN: |
1468-3288 |
Language: |
eng |
Dates: |
Date | Event |
---|
8 May 2018 | Published | 7 June 2017 | Published Online | 27 April 2017 | Accepted |
|
Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
|
PubMed ID: |
28592438 |
Web of Science ID: |
WOS:000433238300020 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/111737 |
Publisher's version: |
https://doi.org/10.1136/gutjnl-2017-314184 |
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