CD14+ CD15− HLA-DR− myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure. Issue 6 (7th June 2017)

• Record Type: Journal Article
• Authors: Bernsmeier, Christine; Triantafyllou, Evangelos; Brenig, Robert; Lebosse, Fanny J; Singanayagam, Arjuna; Patel, Vishal C; Pop, Oltin T; Khamri, Wafa; Nathwani, Rooshi; Tidswell, Robert; Weston, Christopher J; Adams, David H; Thursz, Mark R; Wendon, Julia A; Antoniades, Charalambos Gustav
• Is Part Of: Gut. Volume 67:Issue 6(2018)
• Page Start: 1155
• Page End: 1167
• Publication Date: 2017-06-07
• Subjects: ACLF -- ALF -- cirrhosis -- MDSC -- immune suppression -- bacterial infection; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2017-314184
• Languages: English
• ISSNs: 0017-5749

Abstract

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.