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

Autor:	Bernsmeier C; Institute of Liver Studies, King's College Hospital, King's College London, London, UK.; Liver Biology Laboratory, Cantonal Hospital St. Gallen, St. Gallen, Switzerland., Triantafyllou E; Institute of Liver Studies, King's College Hospital, King's College London, London, UK.; Division of Digestive Diseases, St. Mary's Campus, Imperial College London, London, UK.; Institute of Immunology and Immunotherapy, NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, Birmingham, UK., Brenig R; Liver Biology Laboratory, Cantonal Hospital St. Gallen, St. Gallen, Switzerland., Lebosse FJ; Division of Digestive Diseases, St. Mary's Campus, Imperial College London, London, UK., Singanayagam A; Institute of Liver Studies, King's College Hospital, King's College London, London, UK.; Division of Digestive Diseases, St. Mary's Campus, Imperial College London, London, UK.; Institute of Immunology and Immunotherapy, NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, Birmingham, UK., Patel VC; Institute of Liver Studies, King's College Hospital, King's College London, London, UK., Pop OT; Institute of Liver Studies, King's College Hospital, King's College London, London, UK., Khamri W; Division of Digestive Diseases, St. Mary's Campus, Imperial College London, London, UK., Nathwani R; Division of Digestive Diseases, St. Mary's Campus, Imperial College London, London, UK., Tidswell R; Institute of Liver Studies, King's College Hospital, King's College London, London, UK., Weston CJ; Institute of Immunology and Immunotherapy, NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, Birmingham, UK., Adams DH; Institute of Immunology and Immunotherapy, NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, Birmingham, UK., Thursz MR; Division of Digestive Diseases, St. Mary's Campus, Imperial College London, London, UK., Wendon JA; Institute of Liver Studies, King's College Hospital, King's College London, London, UK., Antoniades CG; Institute of Liver Studies, King's College Hospital, King's College London, London, UK.; Division of Digestive Diseases, St. Mary's Campus, Imperial College London, London, UK.; Institute of Immunology and Immunotherapy, NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, Birmingham, UK.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2018 Jun; Vol. 67 (6), pp. 1155-1167. Date of Electronic Publication: 2017 Jun 07.
DOI:	10.1136/gutjnl-2017-314184
Abstrakt:	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. Competing Interests: Competing interests: None declared. (© 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.)
Databáze:	MEDLINE
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