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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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Increased Expression of CTLA4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure. / Khamri, Wafa; Abeles, Robin D.; Hou, Tie Zheng; Anderson, Amy E.; El-Masry, Ahmed; Triantafyllou, Evangelos; Bernsmeier, Christine; Larsen, Fin S.; Singanayagam, Arjuna; Kudo, Nobuaki; Possamai, Lucia A.; Lebosse, Fanny; Auzinger, Georg; Bernal, William; Willars, Christopher; Weston, Christopher J.; Lombardi, Giovanna; Wendon, Julia; Thursz, Mark; Antoniades, Charalambos G.

In: Gastroenterology, Vol. 153, e8., 28.03.2017, p. 263-276.

Research output: Contribution to journalArticle

Harvard

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, C, Weston, CJ, Lombardi, G, Wendon, J, Thursz, M & Antoniades, CG 2017, 'Increased Expression of CTLA4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure', Gastroenterology, vol. 153, e8., pp. 263-276. https://doi.org/10.1053/j.gastro.2017.03.023

APA

Khamri, W., Abeles, R. D., Hou, T. Z., Anderson, A. E., El-Masry, A., Triantafyllou, E., Bernsmeier, C., Larsen, F. S., Singanayagam, A., Kudo, N., Possamai, L. A., Lebosse, F., Auzinger, G., Bernal, W., Willars, C., Weston, C. J., Lombardi, G., Wendon, J., Thursz, M., & Antoniades, C. G. (2017). Increased Expression of CTLA4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure. Gastroenterology, 153, 263-276. [e8.]. https://doi.org/10.1053/j.gastro.2017.03.023

Vancouver

Khamri W, Abeles RD, Hou TZ, Anderson AE, El-Masry A, Triantafyllou E et al. Increased Expression of CTLA4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure. Gastroenterology. 2017 Mar 28;153:263-276. e8. https://doi.org/10.1053/j.gastro.2017.03.023

Author

Khamri, Wafa ; Abeles, Robin D. ; Hou, Tie Zheng ; Anderson, Amy E. ; El-Masry, Ahmed ; Triantafyllou, Evangelos ; Bernsmeier, Christine ; Larsen, Fin S. ; Singanayagam, Arjuna ; Kudo, Nobuaki ; Possamai, Lucia A. ; Lebosse, Fanny ; Auzinger, Georg ; Bernal, William ; Willars, Christopher ; Weston, Christopher J. ; Lombardi, Giovanna ; Wendon, Julia ; Thursz, Mark ; Antoniades, Charalambos G. / Increased Expression of CTLA4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure. In: Gastroenterology. 2017 ; Vol. 153. pp. 263-276.

Bibtex Download

@article{3e1bb690ca2d40c89efc6cd90155e25e,
title = "Increased Expression of CTLA4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure",
abstract = "Background & Aims Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immuneparesis) 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 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 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 ELISAs. 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 upregulated expression of CTLA4 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 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 upregulates 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.",
keywords = "immune regulation, liver disease, treatment, infection susceptibility",
author = "Wafa Khamri and Abeles, {Robin D.} and Hou, {Tie Zheng} and Anderson, {Amy E.} and Ahmed El-Masry and Evangelos Triantafyllou and Christine Bernsmeier and Larsen, {Fin S.} and Arjuna Singanayagam and Nobuaki Kudo and Possamai, {Lucia A.} and Fanny Lebosse and Georg Auzinger and William Bernal and Christopher Willars and Weston, {Christopher J.} and Giovanna Lombardi and Julia Wendon and Mark Thursz and Antoniades, {Charalambos G.}",
year = "2017",
month = mar,
day = "28",
doi = "10.1053/j.gastro.2017.03.023",
language = "English",
volume = "153",
pages = "263--276",
journal = "Gastroenterology",
issn = "0016-5085",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Increased Expression of CTLA4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure

AU - Khamri, Wafa

AU - Abeles, Robin D.

AU - Hou, Tie Zheng

AU - Anderson, Amy E.

AU - El-Masry, Ahmed

AU - Triantafyllou, Evangelos

AU - Bernsmeier, Christine

AU - Larsen, Fin S.

AU - Singanayagam, Arjuna

AU - Kudo, Nobuaki

AU - Possamai, Lucia A.

AU - Lebosse, Fanny

AU - Auzinger, Georg

AU - Bernal, William

AU - Willars, Christopher

AU - Weston, Christopher J.

AU - Lombardi, Giovanna

AU - Wendon, Julia

AU - Thursz, Mark

AU - Antoniades, Charalambos G.

PY - 2017/3/28

Y1 - 2017/3/28

N2 - Background & Aims Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immuneparesis) 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 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 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 ELISAs. 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 upregulated expression of CTLA4 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 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 upregulates 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.

AB - Background & Aims Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immuneparesis) 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 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 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 ELISAs. 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 upregulated expression of CTLA4 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 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 upregulates 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.

KW - immune regulation

KW - liver disease

KW - treatment

KW - infection susceptibility

U2 - 10.1053/j.gastro.2017.03.023

DO - 10.1053/j.gastro.2017.03.023

M3 - Article

VL - 153

SP - 263

EP - 276

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

M1 - e8.

ER -

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