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CD14+CD15-HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure
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- Journal Article
- Science & Technology
- Life Sciences & Biomedicine
- Gastroenterology & Hepatology
- HEPATOCELLULAR-CARCINOMA PATIENTS
- INNATE IMMUNE-RESPONSES
- MONONUCLEAR-CELLS
- PERIPHERAL-BLOOD
- TLR3 AGONIST
- CIRRHOSIS
- TRANSPLANTATION
- ACTIVATION
- INCREASE
- THERAPY
- 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
- Gastroenterology & Hepatology
- 1103 Clinical Sciences
- 1114 Paediatrics and Reproductive Medicine