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Increased Expression of CTLA4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure

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Title: Increased Expression of CTLA4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure
Authors: Khamri, W
Abeles, RD
Hou, TZ
Anderson, AE
El-Masry, A
Triantafyllou, E
Bernsmeier, C
Larsen, FS
Singanayagam, A
Kudo, N
Possamai, LA
Lebosse, F
Auzinger, G
Bernal, W
Willars, W
Weston, CJ
Lombardi, G
Wendon, J
Thursz, M
Antoniades, C
Item Type: Journal Article
Abstract: BACKGROUND & AIMS : Patients with acute liver failure (ALF) have defe cts in innate immune responses to microbes (immuneparesis) and ar e susceptible to sepsis. Cytotoxic T- lymphocyte associated protein 4 (CTLA4), which inte racts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulato r of T-cell activation. We collected T cells from patients with ALF and investigated wheth er inhibitory signals downregulate 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 w ith acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute d ecompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 hea lthy 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 quantifie d. We measured levels of soluble B7 molecules in supernatants of isolated primary hepat ocytes, 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 an d controls, and mice with acetaminophen-induced liver injury using ELISAs. RESULTS: Peripheral blood samples from patients with ALF had a higher proportion of C D4 + CTLA4 + T cells than controls; patients with infections had the highest proportion s. 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 aga inst CTLA4 increased their proliferative response to antigen a nd to CD3 stimulation, to the same levels as cells from controls. CD4 + T cells from controls upregulated expression of CT LA4 following 24–48 hrs 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 hepat ic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, se creted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contai ned high levels of soluble B7 compared to sera from mice without liver injury. Plasma exch ange 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 expre ssion 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 upregulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces levels of B7 in se ra from patients with ALF and might be used to restore antimicrobial responses to patients.
Issue Date: 28-Mar-2017
Date of Acceptance: 22-Mar-2017
URI: http://hdl.handle.net/10044/1/45811
DOI: https://dx.doi.org/10.1053/j.gastro.2017.03.023
ISSN: 0016-5085
Publisher: Elsevier
Start Page: 263
End Page: 276.e8
Journal / Book Title: Gastroenterology
Volume: 153
Issue: 1
Copyright Statement: © 2017 by the AGA Institute. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).
Sponsor/Funder: Medical Research Council (MRC)
Rosetrees Trust
Funder's Grant Number: MR/K010514/1
M228-F1
Keywords: Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
Immune Regulation
Liver Disease
Treatment
Infection Susceptibility
INFLAMMATORY RESPONSE SYNDROME
COSTIMULATORY MOLECULE
CTLA-4
SEPSIS
INFECTION
IMMUNOTHERAPY
MACROPHAGES
ACTIVATION
DISEASE
HUMANS
Acetaminophen
Acute-On-Chronic Liver Failure
Adaptive Immunity
Adult
Animals
Antibodies
Antigens, CD3
Antigens, CD80
CD4 Lymphocyte Count
CD4-Positive T-Lymphocytes
CTLA-4 Antigen
Cell Proliferation
Cells, Cultured
Chemical and Drug Induced Liver Injury
Coculture Techniques
Dendritic Cells
Hepatocytes
Humans
Liver Cirrhosis
Liver Failure, Acute
Lymphocyte Activation
Mice
Middle Aged
Shock, Septic
1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
1109 Neurosciences
Publication Status: Published
Open Access location: http://www.sciencedirect.com/science/article/pii/S0016508517303323
Appears in Collections:Division of Surgery
Department of Medicine
Faculty of Medicine



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