Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Cancer Risk in Pediatric-Onset Inflammatory Bowel Disease: A Population-Based Danish Cohort Study

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Antibody Responses to Immunization With HCV Envelope Glycoproteins as a Baseline for B cell-Based Vaccine Development

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Crohn's Disease With Progressive Renal Impairment

    Publikation: Bidrag til tidsskriftKommentar/debatForskningpeer review

  4. Safety of Proton Pump Inhibitors Based on a Large, Multi-year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  5. Remission of bile acid malabsorption symptoms following treatment with the glucagon-like peptide 1 receptor agonist liraglutide

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Transcerebral exchange kinetics of large neutral amino acids during acute inspiratory hypoxia in humans

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Artificial liver support in acute and acute-on-chronic liver failure

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Lever- og galdevejssygdomme

    Publikation: Bidrag til bog/antologi/rapportBidrag til bog/antologiFormidling

  4. Meta-analysis of individual patient data of albumin dialysis in acute-on-chronic liver failure: focus on treatment intensity

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  5. Reversal of Acute Liver Failure Due to Wilson Disease by a Regimen of High-Volume Plasma Exchange and Penicillamine

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Wafa Khamri
  • Robin D Abeles
  • Tie Zheng Hou
  • Amy E Anderson
  • Ahmed El-Masry
  • Evangelos Triantafyllou
  • Christine Bernsmeier
  • Fin S Larsen
  • Arjuna Singanayagam
  • Nobuaki Kudo
  • Lucia A Possamai
  • Fanny Lebosse
  • Georg Auzinger
  • William Bernal
  • Christopher Willars
  • Christopher J Weston
  • Giovanna Lombardi
  • Julia Wendon
  • Mark Thursz
  • Charalambos G Antoniades
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftGastroenterology
Vol/bind153
Udgave nummer1
Sider (fra-til)263-276.e8
ISSN0016-5085
DOI
StatusUdgivet - 2017

ID: 52757691