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. 2017 Feb 27:5:21.
doi: 10.1186/s40560-017-0217-0. eCollection 2017.

Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis

Bernt C Hellerud  1   2 , Hilde L Orrem  1 , Knut Dybwik  3 , Søren E Pischke  1 , Andreas Baratt-Due  1 , Albert Castellheim  4 , Hilde Fure  5 , Grethe Bergseth  5 , Dorte Christiansen  5 , Miles A Nunn  6 , Terje Espevik  7 , Corinna Lau  5 , Petter Brandtzæg  2   8 , Erik W Nielsen  3   9 , Tom E Mollnes  1   5   7   9
Affiliations

Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis

Bernt C Hellerud et al. J Intensive Care. .

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-inactivated Neisseria meningitidis administered 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).

Conclusion: 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.

Keywords: Chemokines; Complement; Cytokines; Endotoxin; Immune response; Neisseria meningitidis; Septic shock; Toll-like receptor.

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Figures

Fig. 1
Fig. 1
Upper panel: Complement activation was measured as plasma TCC by multiplex technology at different time points during the experiments (mean with 95% CI). The positive control group and the group treated with coversin and rMIL2 (coversin/rMIL2) contained 12 animals each. Two sham animals are shown for comparison. Lower panel: Complement activity of the classical pathway was measured at different time points by the Complement system Screen WIESLAB® assay (mean with 95% CI). Statistical significance is given for the difference between the positive control and the treatment group
Fig. 2
Fig. 2
Plasma cytokines (INF-γ, TNF, IL-1β, IL-6, IL-8, IL-10, and IL12p40) were measured by multiplex technology at different time points during the experiments (mean with 95% CI) in the same animals as described in the legend to Fig. 1. Statistical significance is given for the difference between the positive control and the treatment group
Fig. 3
Fig. 3
wCD11R3 expression on the surface of granulocytes (mean with 95% CI) was measured by flow cytometry at baseline (Tbasis) and at the end of the experiment (T180) in the same animals as described in the legend to Fig. 1. Statistical significance is given for the difference in MFI between the positive control and the treatment group at T180
See this image and copyright information in PMC

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