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.

Autor:	Khamri W; Division of Digestive Diseases, Imperial College London, United Kingdom. Electronic address: w.khamri@imperial.ac.uk., Abeles RD; Institute of Liver Studies, King's College London, United Kingdom., Hou TZ; Institute of Immunity and Transplantation, University College London, United Kingdom., Anderson AE; Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom., El-Masry A; Division of Digestive Diseases, Imperial College London, United Kingdom., Triantafyllou E; Division of Digestive Diseases, Imperial College London, United Kingdom., Bernsmeier C; Institute of Liver Studies, King's College London, United Kingdom., Larsen FS; Department of Hepatology, Rigshospitalet, Copenhagen, Denmark., Singanayagam A; Institute of Liver Studies, King's College London, United Kingdom., Kudo N; Institute of Reproductive and Developmental Biology, Imperial College London, United Kingdom., Possamai LA; Division of Digestive Diseases, Imperial College London, United Kingdom., Lebosse F; Division of Digestive Diseases, Imperial College London, United Kingdom., Auzinger G; Institute of Liver Studies, King's College London, United Kingdom., Bernal W; Institute of Liver Studies, King's College London, United Kingdom., Willars C; Institute of Liver Studies, King's College London, United Kingdom., Weston CJ; Centre for Liver Research and National Institute for Health Research, Biomedical Research Unit, University of Birmingham, United Kingdom., Lombardi G; Medical Research Council Centre for Transplantation, King's College London, United Kingdom., Wendon J; Institute of Liver Studies, King's College London, United Kingdom., Thursz M; Division of Digestive Diseases, Imperial College London, United Kingdom., Antoniades CG; Division of Digestive Diseases, Imperial College London, United Kingdom; Institute of Liver Studies, King's College London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2017 Jul; Vol. 153 (1), pp. 263-276.e8. Date of Electronic Publication: 2017 Mar 28.
DOI:	10.1053/j.gastro.2017.03.023
Abstrakt:	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. (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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