Publications
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Cavazza A, Triantafyllou E, Savoldelli R, et al., 2024, Macrophage activation markers are associated with infection and mortality in patients with acute liver failure., Liver Int
BACKGROUND AND AIMS: Acute liver failure is a multisystem disorder with a high mortality and frequent need for emergency liver transplantation. Following massive innate immune system activation, soluble markers of macrophage activation are released during liver damage and their association with disease severity and prognosis requires exploration. METHODS: Patients ALF from the United States Acute Liver Failure Study Group (USALFSG, n = 224) and King's College Hospital (n = 40) together with healthy controls (HC, n = 50) were recruited. Serum from early (Days 1-3) and late (>Day 3) time points were analysed for MAMs by enzyme-linked immunosorbent assay correlated to markers of illness severity and 21-day spontaneous survival. Surface expression phenotyping was performed via Flow Cytometry on CD14+ monocytes. RESULTS: All MAMs serum concentrations were significantly higher in ALF compared to controls (p < .0001). sCD206 concentration was higher in early and late stages of the disease in patients with bacteraemia (p = .002) and infection in general (p = .006). In MELD-adjusted multivariate modelling, sCD206 and sCD163 were independently associated with mortality. CD14+ monocyte expression of CD206 (p < .001) was higher in patients with ALF compared with controls and correlated with SOFA score (p = .018). sCD206 was independently validated as a predictor of infection in an external cohort. CONCLUSIONS: sCD206 is increased in serum of ALF patients with infections and poor outcome and is upregulated on CD14+ monocytes. Later measurements of sCD163 and sCD206 during the evolution of ALF have potential as mechanistic predictors of mortality. sCD206 should be explored as a biomarker of sepsis and mortality in ALF.
Gudd C, 2024, Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis, Journal for ImmunoTherapy of Cancer, ISSN: 2051-1426
Gudd C, Mitchell E, Atkinson S, et al., 2024, Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis, Journal for ImmunoTherapy of Cancer, ISSN: 2051-1426
Forlano R, Martinez-Gili L, Takis P, et al., 2024, Disruption of gut barrier integrity and host-microbiome interactions underlie MASLD severity in patients with type-2 diabetes mellitus, Gut Microbes, Vol: 16, ISSN: 1949-0976
Aberration of the “gut-liver axis” contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.Overall, 285 patients were enrolled: 255 serum, 252 urine and 97 stool samples were analyzed. Anaeroplasma and Escherichia/Shigella ASVs were higher, while Butyricicoccus ASVs were lower in those with normal liver. In MASLD±, Butyricicoccus ASV was significantly higher in those with steatosis. In the Fibrosis±, Butyricicoccus ASV was significantly lower in those with fibrosis. Glycochenodeoxycholic acid-3-sulfate (G-UDCA-3S) appeared to be higher in MASLD with fibrosis. Fecal water from patients with MASLD and fibrosis caused the greatest drop in the TEER vs those with normal liver; this was reversed with protease inhibitors. Finally, fecal IL-13 was lower in MASLD with fibrosis. We identified microbiome signatures which were specific for steatosis and fibrosis and independent of other metabolic risk factors. Moreover, we conclude that protease-related gut permeability plays a role in those MASLD patients with fibrosis, and that disease progression is linked to a gut-liver axis which is at least partially independent of T2DM.
Gudd CLC, Sheth R, Thursz MR, et al., 2023, Immune checkpoint inhibitor-induced liver injury, Seminars in Liver Disease, Vol: 43, Pages: 402-417, ISSN: 0272-8087
In recent years cancer treatment has been revolutionized by the development and wide application of checkpoint inhibitor (CPI) drugs, which are a form of immunotherapy. CPI treatment is associated with immune-related adverse events, off-target tissue destructive inflammatory complications, which may affect a range of organs, with liver inflammation (hepatitis) being one of the more commonly noted events. This is a novel form of drug-induced liver injury and a rapidly evolving field, as our understanding of both the basic immunopathology of CPI hepatitis (CPI-H) and optimal clinical management, races to catch up with the increasing application of this form of immunotherapy in clinical practice. In this review, we summarize current evidence and understanding of CPI-H, from fundamental immunology to practical patient management.
Delo J, Forton D, Triantafyllou E, et al., 2023, Peritoneal Immunity in Liver Disease, Livers, Vol: 3, Pages: 240-257
The peritoneum represents a confined microenvironment that has an emerging role as a distinct immunological compartment. In health, this niche is mainly populated by a heterogenous group of macrophages and T lymphocytes but also Natural Killer cells and B lymphocytes. Together they are crucial for immunological surveillance, clearance of infection and resolution of inflammation. Development of ascites is a defining feature of decompensated liver cirrhosis, and spontaneous bacterial peritonitis is the most frequent bacterial infection occurring in this patient group. Recent studies of ascitic fluid have revealed quantitative, phenotypic and functional differences in both innate and adaptive immune cells compared to the healthy state. This review summarises current knowledge of these alterations and explores how the peritoneum in chronic liver disease is simultaneously an immunologically compromised site and yet capable of provoking an intense inflammatory response. A better understanding of this might enable identification of new therapeutic targets aimed to rebalance the peritoneal immunity and reduce the reliance on antimicrobials in an era of increasing antimicrobial resistance.
Cavazza A, Triantafyllou E, Savoldelli R, et al., 2023, Soluble and monocyte surface CD206 is a promising indicator of sepsis in patients with acute liver failure, Publisher: ELSEVIER, Pages: S127-S128, ISSN: 0168-8278
Flint E, Ercan C, Possamai L, et al., 2023, Targeting myeloid-derived suppressor cells in a carbon tetrachloride-induced murine model of chronic liver injury, Publisher: ELSEVIER, Pages: S214-S214, ISSN: 0168-8278
Delo J, Forton D, Triantafyllou E, et al., 2023, The ascitic environment in cirrhosis upregulates the expression of the immune checkpoint CD155 on peritoneal macrophages, Publisher: ELSEVIER, Pages: S452-S452, ISSN: 0168-8278
Patseas D, Mitchell E, Flint E, et al., 2023, Investigating the PD-1/PD-L pathway and macrophage responses in acute-on-chronic liver failure, Publisher: ELSEVIER, Pages: S84-S85, ISSN: 0168-8278
Morrison MA, Artru F, Trovato FM, et al., 2023, Potential therapies for acute-on-chronic liver failure, LIVER INTERNATIONAL, ISSN: 1478-3223
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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
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
Background and Aims: The clinical, prognostic, and therapeutic impact of adrenal insufficiency in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) remains controversial and exact diagnostic criteria are lacking. We sought to determine the diagnostic and therapeutic value of cortisol measurement and glucocorticoid (GC) treatment in ALF and ACLF. Methods: 28-day transplant-free survival (TFS) was studied in relation to absolute cortisol concentrations and to GC treatment in ALF (n = 30) and ACLF (n = 34) patients. Cortisol concentrations and short synacthen test were assessed by chemiluminescence immunoassay and liquid chromatography-mass spectrometry. Clinicians decided independently on GC treatment. In relation, phenotypic and functional characteristics of circulating monocytes were assessed. Results: In ALF, baseline cortisol concentrations <387 nmol/L predicted TFS (sensitivity 83%, specificity 53%). In ACLF, baseline cortisol <392 nmol/L correlated with TFS (sensitivity 80%, specificity 61%). In both, ALF and ACLF, GC treatment did not influence 28-day TFS in patients with low baseline cortisol. However, in patients with baseline cortisol exceeding 387 and 392 nmol/L, respectively, TFS was higher if they had been treated with GC. High baseline cortisol was associated with low HLA-DR expression on monocytes. Conclusion: Our data suggest a prognostic value of baseline cortisol measurement in ALF and ACLF. Overall, strong activation of the hypothalamic–pituitary–adrenal axis indicated poor prognosis. Furthermore, baseline cortisol deserves prospective evaluation as a guide for GC treatment decision-making.
Pop O-T, Geng A, Flint E, et al., 2023, AXL expression on homeostatic resident liver macrophages is reduced in cirrhosis following GAS6 production by hepatic stellate cells, Cellular and Molecular Gastroenterology and Hepatology, Vol: 16, Pages: 17-37, ISSN: 2352-345X
BACKGROUND & AIMS: AXL and MERTK expression on circulating monocytes modulated immune responses in patients with cirrhosis (CD14+HLA-DR+AXL+) and acute-on-chronic liver failure (CD14+MERTK+). AXL expression involved enhanced efferocytosis, sustained phagocytosis, but reduced TNF-α/IL-6 production and T cell activation, suggesting a homeostatic function. Axl was expressed on murine airway in tissues contacting the external environment- but not interstitial lung-, and tissue-resident synovial lining macrophages. We assessed AXL expression on tissue macrophages in patients with cirrhosis. METHODS: Using multiplexed immunofluorescence we compared AXL expression in liver biopsies in cirrhosis (n=22), chronic liver disease (n=8), non-cirrhotic portal hypertension (n=4) and healthy controls (n=4). Phenotype and function of isolated primary human liver macrophages were characterised by flow cytometry (cirrhosis, n=11; control, n=14) ex vivo. Also, AXL expression was assessed on peritoneal- (n=29) and gut macrophages (n=16) from cirrhotic patients. Regulation of AXL expression was analysed in vitro and ex vivo using primary hepatic stellate cells (HSCs), LX-2 cells and GAS6 in co-culture experiments. RESULTS: AXL was expressed on resident (CD68+) but not tissue-infiltrating (MAC387+) liver macrophages, hepatocytes, HSCs, or sinusoidal endothelial cells. Prevalence of hepatic CD68+AXL+ cells significantly decreased with cirrhosis progression: (Healthy 90.2%; Child Pugh A 76.1%; B 64.5%; C 18.7%, all p<0.05) and negatively correlated with MELD and CRP (all p<0.05). AXL-expressing hepatic macrophages were CD68highHLA-DRhighCD16highCD206high. AXL expression also decreased on gut and peritoneal macrophages from cirrhotic patients, but increased in regional lymph nodes. GAS6, enriched in the cirrhotic liver, appeared to be secreted by HSCs and down-regulate AXL in vitro. CONCLUSIONS: Decreased AXL expression on resident liver macrophages in advanced cirrhosis, pote
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
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
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, The International Liver CongressTM 2022, Publisher: Elsevier, Pages: S674-S675, 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
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, 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
Ghani R, Blanco JM, Forlano R, et al., 2022, RELATIVE CHANGE OF <i>ENTEROCOCCUS FAECIUM</i>, 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
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, Digestive Disease Week® (DDW) 2022, Publisher: Elsevier, Pages: S1136-S1136, 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
<jats:sec> <jats:title>Background & Aims</jats:title> <jats:p>Acute‐on‐chronic liver failure (ACLF) is characterized by systemic inflammation, monocyte dysfunction, and susceptibility to infection. Lysophosphatidylcholines (LPCs) are immune‐active lipids whose metabolic regulation and effect on monocyte function in ACLF is open for study.</jats:p> </jats:sec> <jats:sec> <jats:title>Approaches & Results</jats:title> <jats:p>Three hundred forty‐two subjects were recruited and characterized for blood lipid, cytokines, phospholipase (PLA), and autotaxin (ATX) concentration. Peripheral blood mononuclear cells and CD14<jats:sup>+</jats:sup> monocytes were cultured with LPC, or its autotaxin (ATX)‐derived product, lysophosphatidic acid (LPA), with or without lipopolysaccharide stimulation and assessed for surface marker phenotype, cytokines production, ATX and LPA‐receptor expression, and phagocytosis. Hepatic ATX expression was determined by immunohistochemistry. Healthy volunteers and patients with sepsis or acute liver failure served as controls. ACLF serum was depleted in LPCs with up‐regulated LPA levels. Patients who died had lower LPC levels than survivors (area under the receiver operating characteristic curve, 0.94; <jats:italic toggle="yes">P</jats:italic> < 0.001). Patients with high‐grade ACLF had the lowest LPC concentrations and these rose over the first 3 days of admission. ATX concentrations were higher in patients with AD and ACLF and correlated with Model for End‐Stage Liver Disease, Consortium on Chronic Liver Failure–Sequential Organ Failure Assessment, and LPC/LPA concentrations. Reduction in LPC correlated with higher monocyte Mer‐tyrosine‐kinase (MerTK) and CD163 expression. Plasma ATX concentrations rose dynamically during ACLF evolution, correlating wi
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, 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
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