Publications
67 results found
Trovato FM, Zia R, Artru F, et al., 2023, Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure., Journal of Hepatology, Vol: 78, Pages: 558-573, ISSN: 0168-8278
BACKGROUND AND AIMS: Acute liver failure (ALF) is a life-threatening disease characterised by high-grade inflammation and immunoparesis with a high incidence of death from sepsis. Here, we aimed to describe the metabolic dysregulation in ALF and determine whether systemic immune responses are modulated via the lysophosphatidylcholine(LPC)-autotaxin(ATX)-lysophosphatidylcholinic acid (LPA) pathway. METHODS: 96 ALF patients, 71 healthy controls (HC), 104 patients with cirrhosis and 31 septic patients were recruited. The pathways of interest were identified based on multivariate statistical analysis of proton nuclear magnetic resonance (1HNMR) spectroscopy, untargeted ultraperformance liquid chromatography-mass spectrometry (UPLC-MS)-based lipidomics and validated with a targeted metabolomics panel. Peripheral blood mononuclear cells were cultured with LPA 16:0, 18:0, 18:1, and their immune checkpoint surface expression was assessed by flow cytometry. LPA receptor (LPAR) transcript-level expression of monocytes was investigated and the effect of LPAR antagonism was also examined in vitro. RESULTS: LPC 16:0 was found highly discriminant between ALF and HC. There was an increase in ATX and LPA in ALF compared to HC and sepsis. LPCs 16:0, 18:0 and 18:1 were reduced in ALF patients with poor prognosis. Treatment of monocytes with LPA 16:0 increased their PD-L1 expression and reduced CD155, CD163, MerTK levels, without effect on T and NK/CD56+T cells immune checkpoints. LPAR1 and 3 antagonism in culture reversed the LPA effect on monocyte expression of MerTK and CD163. MerTK and CD163, but not LPARs genes, were differently expressed and upregulated in monocytes from ALF patients compared to controls. CONCLUSION: Reduced amounts of LPCs are biomarkers of poor prognosis in patients with ALF. The LPC-ATX-LPA axis appears to modulate innate immune response in ALF via LPAR1 and LPAR3. Further investigations are required to identify novel therapeutic agents targeting these recept
Morrison MA, Artru F, Trovato FM, et al., 2023, Potential therapies for acute-on-chronic liver failure., Liver Int
Acute-on-chronic liver failure (ACLF) is a syndrome that develops in approximately 30% of patients hospitalised with cirrhosis and is characterised by an acute decompensation of liver function associated with extra-hepatic organ failures and a high short-term mortality. At present, no specific therapies are available for ACLF, and current management is limited to treatment of the precipitating event and organ support. Given the high prevalence and high mortality of this severe liver disease, there is an urgent need for targeted treatments. There is increasing evidence of the important role played by systemic inflammation and immune dysfunction in the pathophysiology of ACLF and a better understanding of these immune processes is resulting in new therapeutic targets. The aim of this review is to present an overview of ongoing studies of potentially promising therapies and how they could be utilised in the management of ACLF.
Roth S, Flint E, Ghataore L, et al., 2023, Low Baseline but Not Delta Cortisol Relates to 28-Day Transplant-Free Survival in Acute and Acute-on-Chronic Liver Failure, Gastro Hep Advances, Vol: 2, Pages: 72-82, ISSN: 2772-5723
Trovato F, Zia R, Artru F, et al., 2022, LYSOPHOSPHATIDYLCHOLINES ARE ASSOCIATED WITH MORTALITY IN ACUTE LIVER FAILURE AND MODULATE IMMUNE CHECKPOINT EXPRESSION IN MONOCYTES, Publisher: WILEY, Pages: S1230-S1231, ISSN: 0270-9139
Flint E, Ercan C, Possamai L, et al., 2022, Expansion of MDSC in the liver in a CCl4 mouse model of cirrhosis, Publisher: E M H SWISS MEDICAL PUBLISHERS LTD, Pages: 12S-12S, ISSN: 1424-7860
Delo J, Forton D, Triantafyllou E, et al., 2022, EXPRESSION OF THE IMMUNE CHECKPOINTS CD96 AND CD226 ON ASCITIC IMMUNE CELLS IN PATIENTS WITH DECOMPENSATED LIVER DISEASE DENOTES A MORE IMMUNOSUPPRESSIVE PHENOTYPE, Publisher: BMJ PUBLISHING GROUP, Pages: A15-A16, ISSN: 0017-5749
Flint E, Triantafyllou E, Ercan C, et al., 2022, Expansion of hepatic myeloid-derived suppressor cells in a carbon tetrachloride murine model of cirrhosis, Publisher: E M H SWISS MEDICAL PUBLISHERS LTD, Pages: 25S-25S, ISSN: 1424-7860
Trovato FM, Mujib S, Artru F, et al., 2022, The prognostic role of lysophosphatidylcholines and their immunomodulatory potential in acute liver failure, International Liver Congress, Publisher: ELSEVIER, Pages: S116-S116, ISSN: 0168-8278
Artru F, Atkinson S, Forrest E, et al., 2022, Untargeted lipidomics differentiate ACLF precipitated by severe alcoholic hepatitis, Publisher: ELSEVIER, Pages: S352-S353, ISSN: 0168-8278
Forlano R, Mullish BH, Martinez-Gili L, et al., 2022, Factors associated with increased gut permeability and severity of liver disease in diabetic patients with NAFLD, Publisher: ELSEVIER, Pages: S674-S675, ISSN: 0168-8278
Artru F, Atkinson S, Trovato F, et al., 2022, Untargeted lipidomics unveils a specific plasma signature of severe alcoholic hepatitis, International Liver Congress, Publisher: ELSEVIER, Pages: S135-S135, ISSN: 0168-8278
Forlano R, Mullish BH, Martinez-Gili L, et al., 2022, FACTORS ASSOCIATED WITH INCREASED GUT PERMEABILITY AND SEVERITY OF LIVER DISEASE IN DIABETIC PATIENTS WITH NAFLD, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S1136-S1136, ISSN: 0016-5085
Ghani R, Blanco JM, Forlano R, et al., 2022, RELATIVE CHANGE OF ENTEROCOCCUS FAECIUM, SELECTED COMMENSAL BACTERIA AND CYTOKINES ARE SEEN IN PATIENTS COLONIZED WITH MULTIDRUG-RESISTANT ORGANISMS WHO UNDERGO INTESTINAL MICROBIOTA TRANSPLANTATION, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S218-S219, ISSN: 0016-5085
Artru F, McPhail MJW, Triantafyllou E, et al., 2022, Lipids in liver failure syndromes: a focus on eicosanoids, specialized pro-resolvinglipid mediators and lysophospholipids., Frontiers in Immunology, Vol: 13, Pages: 1-21, ISSN: 1664-3224
Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described.
Flint E, Triantafyllou E, Bernsmeier C, 2022, TAM receptors in the pathophysiology of liver disease, Livers, Vol: 2, Pages: 15-29, ISSN: 2673-4389
TAM receptors (Tyro3, Axl and MerTK) are a family of tyrosine kinase receptors that are expressed in a variety of cell populations, including liver parenchymal and non-parenchymal cells. These receptors are vital for immune homeostasis, as they regulate the innate immune response by suppressing inflammation via toll-like receptor inhibition and by promoting tissue resolution through efferocytosis. However, there is increasing evidence indicating that aberrant TAM receptor signaling may play a role in pathophysiological processes in the context of liver disease. This review will explore the roles of TAM receptors and their ligands in liver homeostasis as well as a variety of disease settings, including acute liver injury, steatosis, fibrosis, cirrhosis-associated immune dysfunction and hepatocellular carcinoma. A better understanding of our current knowledge of TAM receptors in liver disease may identify new opportunities for disease monitoring as well as novel therapeutic targets. Nonetheless, this review also aims to highlight areas where further research on TAM receptor biology in liver disease is required.
Cavazza A, Huang X, Triantafyllou E, et al., 2021, OSTEOPONTIN, MACROPHAGE MANNOSE RECEPTOR AND SOLUBLE PD-L1 ARE UPREGULATED MACROPHAGE ACTIVATION MARKERS IN PATIENTS WITH ACUTE LIVER FAILURE, Publisher: WILEY, Pages: 164A-165A, ISSN: 0270-9139
Roth S, Flint E, Ghataore L, et al., 2021, Low baseline but not delta cortisol relates to 28-day transplant-free survival in acute liver failure syndromes, Publisher: E M H SWISS MEDICAL PUBLISHERS LTD, Pages: 25-25, ISSN: 1424-7860
Khamri W, Gudd C, Liu T, et al., 2021, Suppressor CD4+ T cells expressing HLA-G are expanded in the peripheral blood from patients with acute decompensation of cirrhosis, Gut, Vol: 71, Pages: 1192-1202, ISSN: 0017-5749
Objective Identifying components of immuneparesis, a hallmark of chronic liver failure, is crucial for our understanding of complications in cirrhosis. Various suppressor CD4+ T cells have been established as potent inhibitors of systemic immune activation. Here, we establish the presence, regulation and mechanism of action of a suppressive CD4+ T cell subset expressing human leucocyte antigen G (HLA-G) in patients with acute decompensation of cirrhosis (AD).Design Flow cytometry was used to determine the proportion and immunophenotype of CD4+HLA-G+ T cells from peripheral blood of 20 healthy controls (HCs) and 98 patients with cirrhosis (28 with stable cirrhosis (SC), 20 with chronic decompensated cirrhosis (CD) and 50 with AD). Transcriptional and functional signatures of cell-sorted CD4+HLA-G+ cells were delineated by NanoString technology and suppression assays, respectively. The role of immunosuppressive cytokine interleukin (IL)-35 in inducing this population was investigated through in vitro blockade experiments. Immunohistochemistry (IHC) and cultures of primary human Kupffer cells (KCs) were performed to assess cellular sources of IL-35. HLA-G-mediated T cell suppression was explored using neutralising antibodies targeting co-inhibitory pathways.Results Patients with AD were distinguished by an expansion of a CD4+HLA-G+CTLA-4+IL-35+ immunosuppressive population associated with disease severity, clinical course of AD, infectious complications and poor outcome. Transcriptomic analyses excluded the possibility that these were thymic-derived regulatory T cells. IHC analyses and in vitro cultures demonstrate that KCs represent a potent source of IL-35 which can induce the observed HLA-G+ phenotype. These exert cytotoxic T lymphocyte antigen-4-mediated impaired responses in T cells paralleled by an HLA-G-driven downregulation of T helper 17-related cytokines.Conclusion We have identified a cytokine-driven peripherally derived suppressive population that may contr
Trovato FM, Zia R, Napoli S, et al., 2021, Dysregulation of the Lysophosphatidylcholine/Autotaxin/Lysophosphatidic Acid Axis in Acute‐on‐Chronic Liver Failure Is Associated With Mortality and Systemic Inflammation by Lysophosphatidic Acid–Dependent Monocyte Activation, Publisher: Ovid Technologies (Wolters Kluwer Health), Pages: 907-925, ISSN: 0270-9139
Roth S, Flint E, Ghataore L, et al., 2021, Low baseline cortisol but not delta cortisol relates to 28-day transplant-free survival in acute liver failure syndromes, Publisher: ELSEVIER, Pages: S306-S306, ISSN: 0168-8278
Gudd CLC, Antoniades CG, Turajlic S, et al., 2021, CCR2+monocytes induce hepatic accumulation and activation of tissue destructive CD8+T cells in a murine model of checkpoint inhibitor-induced hepatitis, Publisher: ELSEVIER, Pages: S224-S225, ISSN: 0168-8278
Triantafyllou E, Trovato F, Husbyn H, et al., 2021, PD-L1 expression of monocytes relates to severity, infection and mortality in acute-on-chronic liver failure, Publisher: ELSEVIER, Pages: S208-S208, ISSN: 0168-8278
Gudd CLC, Au L, Triantafyllou E, et al., 2021, Activation and transcriptional profile of monocytes and CD8+ T cells are altered in checkpoint inhibitor-related hepatitis, Journal of Hepatology, Vol: 75, Pages: 177-189, ISSN: 0168-8278
Singanayagam A, Triantafyllou E, 2021, Macrophages in Chronic Liver Failure: Diversity, Plasticity and Therapeutic Targeting, Frontiers in Immunology, Vol: 12
<jats:p>Chronic liver injury results in immune-driven progressive fibrosis, with risk of cirrhosis development and impact on morbidity and mortality. Persistent liver cell damage and death causes immune cell activation and inflammation. Patients with advanced cirrhosis additionally experience pathological bacterial translocation, exposure to microbial products and chronic engagement of the immune system. Bacterial infections have a high incidence in cirrhosis, with spontaneous bacterial peritonitis being the most common, while the subsequent systemic inflammation, organ failure and immune dysregulation increase the mortality risk. Tissue-resident and recruited macrophages play a central part in the development of inflammation and fibrosis progression. In the liver, adipose tissue, peritoneum and intestines, diverse macrophage populations exhibit great phenotypic and functional plasticity determined by their ontogeny, epigenetic programming and local microenvironment. These changes can, at different times, promote or ameliorate disease states and therefore represent potential targets for macrophage-directed therapies. In this review, we discuss the evidence for macrophage phenotypic and functional alterations in tissue compartments during the development and progression of chronic liver failure in different aetiologies and highlight the potential of macrophage modulation as a therapeutic strategy for liver disease.</jats:p>
Triantafyllou E, Gudd CLC, Mawhin M-A, et al., 2021, PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury, Journal of Clinical Investigation, Vol: 131, ISSN: 0021-9738
Pop O-T, Brenig RG, Triantafyllou E, et al., 2020, AXL-expressing homeostatic liver macrophages are reduced in patients with progression of cirrhosis, Publisher: ELSEVIER, Pages: S30-S31, ISSN: 0168-8278
Brenig R, Pop OT, Triantafyllou E, et al., 2020, Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis, Life Science Alliance, Vol: 3, Pages: 1-16, ISSN: 2575-1077
Infectious complications in patients with cirrhosis frequently initiate episodes of decompensation and substantially contribute to the high mortality. Mechanisms of the underlying immuneparesis remain underexplored. TAM receptors (TYRO3/AXL/MERTK) are important inhibitors of innate immune responses. To understand the pathophysiology of immuneparesis in cirrhosis, we detailed TAM receptor expression in relation to monocyte function and disease severity prior to the onset of acute decompensation. TNF-α/IL-6 responses to lipopolysaccharide were attenuated in monocytes from patients with cirrhosis (n = 96) compared with controls (n = 27) and decreased in parallel with disease severity. Concurrently, an AXL-expressing (AXL+) monocyte population expanded. AXL+ cells (CD14+CD16highHLA-DRhigh) were characterised by attenuated TNF-α/IL-6 responses and T cell activation but enhanced efferocytosis and preserved phagocytosis of Escherichia coli. Their expansion correlated with disease severity, complications, infection, and 1-yr mortality. AXL+ monocytes were generated in response to microbial products and efferocytosis in vitro. AXL kinase inhibition and down-regulation reversed attenuated monocyte inflammatory responses in cirrhosis ex vivo. AXL may thus serve as prognostic marker and deserves evaluation as immunotherapeutic target in cirrhosis.
Lebosse F, Gudd C, Tunc E, et al., 2019, CD8+ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction, EBioMedicine, Vol: 49, Pages: 258-268, ISSN: 2352-3964
BackgroundCirrhosis-associated immune dysfunction (CAID) contributes to high sepsis risk in patients with chronic liver disease. Various innate and; to a lesser extent; adaptive immune dysfunctions have been described as contributors to CAID leading to immune-paresis and impaired anti-microbial response in cirrhosis. In this study, we examined the phenotype of CD8+ T cells in chronic liver disease with the aim to evaluate changes that might contribute to impaired immune responses.MethodsSixty patients with cirrhosis were prospectively recruited for this study. CD8+ T cells from peripheral blood, ascites and liver explants were characterized using flow cytometry and immunohistochemistry, respectively. The transcriptional signature of flow-sorted HLA-DR+CD8+ T cells was performed using Nanostring™ technology. HLA-DR+CD8+ T cells interactions with PBMCs and myeloid cells were tested in vitro.FindingsPeripheral CD8+ T cells from cirrhotic patients displayed an altered phenotype characterized by high HLA-DR and TIM-3 surface expression associated with concomitant infections and disease severity, respectively. Paired peritoneal CD8+ T cells expressed more pronounced levels of HLA-DR and PD-1 compared to peripheral CD8+ T cells. HLA-DR+CD8+ T cells were enriched in cirrhotic livers compared to controls. TIM-3, CTLA-4 and PD-1 levels were highly expressed on HLA-DR+CD8+ T cells and co-expression of HLA-DR and PD1 was higher in patients with poor disease outcomes. Genes involved in cytokines production and intracellular signalling pathways were strongly down-regulated in HLA-DR+CD8+ T cells. In comparison to their HLA-DR− counterparts, HLA-DR+CD8+ T cells promoted less proliferation of PBMCs and induced phenotypic and functional dysfunctions in monocytes and neutrophils in vitro.InterpretationIn patients with cirrhosis, CD8+ T cells display a phenotypic, functional and transcriptional profile which may contribute to CAID.FundThis work was supported by Medical Res
Ong DJ, Hall A, Triantafyllou E, et al., 2019, Expression of Secretory Leukocyte Protease Inhibitor (SLPI) Detected by Immunohistochemistry in Hepatocellular and Cholangiocellular Tumours, 12th Joint Meeting of the British-Division-of-the-International-Academy-of-Pathology and the Pathological-Society-of-Great-Britain-and-Ireland (Leeds Pathology), Publisher: WILEY, Pages: S45-S45, ISSN: 0022-3417
Pop OT, Brenig RG, Triantafyllou E, et al., 2019, AXL-expressing immune-homeostatic liver macrophages disappear in progressive cirrhosis, Publisher: E M H SWISS MEDICAL PUBLISHERS LTD, Pages: 22S-22S, ISSN: 1424-7860
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