Journal
GUT
Volume 67, Issue 6, Pages 1155-1167Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2017-314184
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Funding
- Medical Research Council (MRC) [MR/K010514/1]
- European Association for the Study of the Liver
- Rosetrees Charitable Trust
- Stoneygate Charitable Trust
- Sheila Sherlock Fellowship of theEuropean Association for the Study of the Liver
- Swiss National Science Foundation grant (SNSF Grant) [320030_159984]
- MRC [G0700301, MR/M009157/1, G0802577, G0300102, MR/K010514/1, G0400496, G0300101, MC_PC_14123] Funding Source: UKRI
- Medical Research Council [MR/M009157/1, MC_PC_14123, G0300102, G0802577, G0400496, MR/K010514/1, G0700301, G0300101] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0616-10012, NF-SI-0512-10080] Funding Source: researchfish
- Rosetrees Trust [M115-F2] Funding Source: researchfish
- Swiss National Science Foundation (SNF) [320030_159984] Funding Source: Swiss National Science Foundation (SNF)
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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.
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