title: Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis.
abstract: BACKGROUND
  Fulminant meningococcal sepsis, characterized by overwhelming innate immune activation, mostly affects young people and causes high mortality. This study aimed to investigate the effect of targeting two key molecules of innate immunity, complement component C5, and co-receptor CD14 in the Toll-like receptor system, on the inflammatory response in meningococcal sepsis.
  
  
  METHODS
  Meningococcal sepsis was simulated by continuous intravenous infusion of an escalating dose of heat-inactivatedNeisseria meningitidisadministered over 3 h. The piglets were randomized, blinded to the investigators, to a positive control group (n= 12) receiving saline and to an interventional group (n= 12) receiving a recombinant anti-CD14 monoclonal antibody together with the C5 inhibitor coversin.
  
  
  RESULTS
  A substantial increase in plasma complement activation in the untreated group was completely abolished in the treatment group (p= 0.006). The following inflammatory mediators were substantially reduced in plasma in the treatment group: Interferon-γ by 75% (p= 0.0001), tumor necrosis factor by 50% (p= 0.01), Interleukin (IL)-8 by 50% (p= 0.03), IL-10 by 40% (p= 0.04), IL-12p40 by 50% (p= 0.03), and granulocyte CD11b (CR3) expression by 20% (p= 0.01).
  
  
  CONCLUSIONS
  Inhibition of C5 and CD14 may be beneficial in attenuating the detrimental effects of complement activation and modulating the cytokine storm in patients with fulminant meningococcal sepsis.
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, and K.G. Jebsen IRC, University of Oslo, N-0027 Oslo, Norway.|Department of Pediatrics, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway.
authors.forename: Bernt C
authors.initials: BC
authors.lastname: Hellerud
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, and K.G. Jebsen IRC, University of Oslo, N-0027 Oslo, Norway.
authors.forename: Hilde L
authors.initials: HL
authors.lastname: Orrem
authors.affiliation: Department of Anesthesiology, Nordland Hospital and Nord University, Bodø, Norway.
authors.forename: Knut
authors.initials: K
authors.lastname: Dybwik
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, and K.G. Jebsen IRC, University of Oslo, N-0027 Oslo, Norway.
authors.forename: Søren E
authors.initials: SE
authors.lastname: Pischke
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, and K.G. Jebsen IRC, University of Oslo, N-0027 Oslo, Norway.
authors.forename: Andreas
authors.initials: A
authors.lastname: Baratt-Due
authors.affiliation: Department of Anesthesiology and Intensive Care Unit, Institution of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Albert
authors.initials: A
authors.lastname: Castellheim
authors.affiliation: Research Laboratory, Nordland Hospital, Bodø, Norway.
authors.forename: Hilde
authors.initials: H
authors.lastname: Fure
authors.affiliation: Research Laboratory, Nordland Hospital, Bodø, Norway.
authors.forename: Grethe
authors.initials: G
authors.lastname: Bergseth
authors.affiliation: Research Laboratory, Nordland Hospital, Bodø, Norway.
authors.forename: Dorte
authors.initials: D
authors.lastname: Christiansen
authors.affiliation: Akari Therapeutics Plc, London, UK.
authors.forename: Miles A
authors.initials: MA
authors.lastname: Nunn
authors.affiliation: Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Terje
authors.initials: T
authors.lastname: Espevik
authors.affiliation: Research Laboratory, Nordland Hospital, Bodø, Norway.
authors.forename: Corinna
authors.initials: C
authors.lastname: Lau
authors.affiliation: Department of Pediatrics, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Petter
authors.initials: P
authors.lastname: Brandtzæg
authors.affiliation: Department of Anesthesiology, Nordland Hospital and Nord University, Bodø, Norway.|Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway.
authors.forename: Erik W
authors.initials: EW
authors.lastname: Nielsen
authors.affiliation: Department of Immunology, Oslo University Hospital Rikshospitalet, and K.G. Jebsen IRC, University of Oslo, N-0027 Oslo, Norway.|Research Laboratory, Nordland Hospital, Bodø, Norway.|Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway.
authors.forename: Tom E
authors.initials: TE
authors.lastname: Mollnes
keywords: Chemokines; Complement; Cytokines; Endotoxin; Immune response; Neisseria meningitidis; Septic shock; Toll-like receptor