Increased Expression of Cytotoxic T-Lymphocyte-Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure.

BACKGROUND & AIMS: Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulator of T-cell activation. We collected T cells from patients with ALF and investigated whether inhibitory signals down-regulate adaptive immune responses in patients with ALF. METHODS: We collected peripheral blood mononuclear cells from patients with ALF and controls from September 2013 through September 2015 (45 patients with ALF, 20 patients with acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute decompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 healthy individuals). Circulating CD4+ T cells were isolated and analyzed by flow cytometry. CD4+ T cells were incubated with antigen, or agonist to CD3 and dendritic cells, with or without antibody against CTLA4; T-cell proliferation and protein expression were quantified. We measured levels of soluble B7 molecules in supernatants of isolated primary hepatocytes, hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood samples from patients with ALF had a higher proportion of CD4+ CTLA4+ T cells than controls; patients with infections had the highest proportions. CD4+ T cells from patients with ALF had a reduced proliferative response to antigen or CD3 stimulation compared to cells from controls; incubation of CD4+ T cells from patients with ALF with an antibody against CTLA4 increased their proliferative response to antigen and to CD3 stimulation, to the same levels as cells from controls. CD4+ T cells from controls up-regulated expression of CTLA4 after 24-48 hours culture with sera from patients with ALF; these sera were found to have increased concentrations of soluble B7 compared to sera from controls. Necrotic human primary hepatocytes exposed to acetaminophen, but not hepatic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, secreted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells. CONCLUSIONS: Peripheral CD4+ T cells from patients with ALF have increased expression of CTLA4 compared to individuals without ALF; these cells have a reduced response to antigen and CD3 stimulation. We found sera of patients with ALF and from mice with liver injury to have high concentrations of soluble B7, which up-regulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces levels of B7 in sera from patients with ALF and might be used to restore antimicrobial responses to patients

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MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure.

OBJECTIVE: Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. DESIGN: Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer-/-) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. RESULTS: We demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer-/- mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance. CONCLUSIONS: We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury

Immunotherapy in the treatment and prevention of infection in acute-on-chronic liver failure

Chronic liver disease, depicted by gradual destruction and fibrosis of the liver, is a condition with high and probably increasing prevalence worldwide. Its deterioration, acute-on-chronic liver failure (ACLF), is characterized by an in-hospital mortality of up to 65%. Infectious complications are the main precipitants eliciting ACLF and concurrently the main cause of death from ACLF. Patients have a marked susceptibility to bacterial infections, which is thought to arise a consequence of an inadequate immune response to microbial challenge, termed immuneparesis. The pathophysiologic mechanisms remain poorly understood. Treatments aimed at restoring the patients’ immune function may prevent onset of ACLF and death from secondary infections. A number of drugs approved for patients with liver disease bear immunomodulatory potential such as albumin, glucocorticoids, N-acetylcysteine. Specific targets have been defined that may lead to development of new immunotherapeutic agents. Here, we summarize the pathophysiology of immuneparesis in ACLF and drug candidates to restore immune function and improve survival in the future.</jats:p

Short-term treatment with L-arginine prevents the smoking-induced impairment of endothelial function and vascular elastic properties in young individuals

Background: L-arginine, the substrate for endothelial nitric oxide synthase, is essential for normal endothelial function. Aim of the present study was to investigate in healthy smokers the effect of a short-term daily L-arginine administration on vascular function. Methods: We studied the effect of a 3-day oral administration of L-arginine in 10 healthy smokers (24.3 +/- 0.73 years old) on 3 occasions (day0, day1 and day3). The study was carried out on two separate arms, one with L-arginine (7 gr/d) and one with placebo according to a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before, immediately after (Sm0) and 20 min after (Sm20) cigarette smoking. Endothelial function was evaluated by flow-mediated dilatation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections. Results: Compared to placebo, L-arginine led to an increase of FMD (p&lt;0.05 at day 2), indicating a favorable effect on endothelial function, which however lost significance at day 3. L-arginine induced a progressive decrease of PWV and AIx at both day 2 and day 3 (p&lt;0.01 vs baseline for all). L-arginine blunted the acute smoking-induced increase of AIx at both day 1 (p&lt;0.05) and day 3 (p&lt;0.01), and there was a trend to protect the smoking-induced change of PWV at day 3 (p&lt;0.1). Conclusions: Short-term daily administration of L-arginine improves arterial performance in healthy smokers and abrogates the smoking-induced increase in arterial stiffness and wave reflections in these individuals. (C) 2007 Elsevier Ireland Ltd. All rights reserved

New biochemical markers in acute coronary syndromes

This article comments on the role of the most important biochemical markers that are already applied in clinical practice or are still under research, in Acute Coronary Syndromes (ACS). Cardiac troponin (cTn) is established as the ‘gold standard’ in the diagnosis of ACS. C-reactive protein (CRP) and especially high-sensitivity CRP (hs-CRP) are considered to be the most useful inflammatory markers for clinical practice in the setting of acute coronary syndrome. Brain-type natriuretic peptide (BNP) and the amino terminal fragment of the prohormone BNP (NT-proBNP) appear to provide prognostic information in individuals admitted for acute coronary syndromes. Microalbuminuria in nondiabetics appears to be a signal from the kidney that the vasculature, particularly the endothelium, is not functioning properly. Increased plasma levels of cystatin C, neopterin, myeloperoxidase, and pregnancy associated protein are associated with adverse cardiovascular outcomes, cardiovascular and noncardiovascular death, and possibly cerebrovascular disease. Furthermore, recent evidence suggests that serum levels of CD40-CD40L pathway exert important roles in progression, and outcome of acute coronary syndrome. In the future further, studies are necessary to elucidate the exact role of the new biochemical markers in ACS