Combined inhibition of complement and CD14 efficiently attenuated the inflammatory response induced by Staphylococcus aureus in a human whole blood model

Skjeflo, Espen Waage; Christiansen, Dorte; Lambris, John D.; Espevik, Terje; Mollnes, Tom Eirik

doi:10.1016/j.imbio.2012.08.068

Cited by 7 publications

(8 citation statements)

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“…In this context, compstatin has shown consistent efficacy in blocking inflammatory and procoagulant reactions in a human whole blood model of bacterial inflammation that closely resembles acute septicaemia [65][66][67][68]. Furthermore, recent studies have suggested that anti-CD14 treatment might confer additive protection against LPS shock or Gram-positive or polymicrobial bacterial challenge, when combined with C3 or C5 inhibition [69][70][71].…”

Section: Probing the Therapeutic Efficacy Of Compstatin Analogues In mentioning

confidence: 99%

Compstatin: a C3‐targeted complement inhibitor reaching its prime for bedside intervention

Mastellos

Yancopoulou²,

Kokkinos³

et al. 2015

Eur J Clin Investigation

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There is a growing awareness that complement plays an integral role in human physiology and disease, transcending its traditional perception as an accessory system for pathogen clearance and opsonic cell killing. As the list of pathologies linked to dysregulated complement activation grows longer, it has become clear that targeted modulation of this innate immune system opens new windows of therapeutic opportunity for anti-inflammatory drug design. Indeed, the introduction of the first complement-targeting drugs has reignited a vibrant interest in the clinical translation of complement-based inhibitors. Compstatin was discovered as a cyclic peptide that inhibits complement activation by binding C3 and interfering with convertase formation and C3 cleavage. As the convergence point of all activation pathways and a molecular hub for crosstalk with multiple pathogenic pathways, C3 represents an attractive target for therapeutic modulation of the complement cascade. A multidisciplinary drug optimization effort encompassing rational “wet” and in silico synthetic approaches and an array of biophysical, structural, and analytical tools has culminated in an impressive structure-function refinement of compstatin, yielding a series of analogs that show promise for a wide spectrum of clinical applications. These new derivatives have improved inhibitory potency and pharmacokinetic profiles and show efficacy in clinically relevant primate models of disease. This review provides an up-to-date survey of the drug design effort placed on the compstatin family of C3 inhibitors, highlighting the most promising drug candidates. It also discusses translational challenges in complement drug discovery and peptide drug development and reviews concerns related to systemic C3 interception.

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Section: Probing the Therapeutic Efficacy Of Compstatin Analogues In mentioning

confidence: 99%

Compstatin: a C3‐targeted complement inhibitor reaching its prime for bedside intervention

Mastellos

Yancopoulou²,

Kokkinos³

et al. 2015

Eur J Clin Investigation

Self Cite

188

231

View full text Add to dashboard Cite

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“…The effect of complement and CD14 inhibition on Grampositive bacteria is sparsely evaluated. One study using various strains of Staphylococcus aureus in a human whole-blood model demonstrated that simultaneous inhibition of CD14 and complement efficiently reduced the inflammatory response [78]. However, and contrary to Gram-negative-induced inflammation, the responses were primarily dependent on complement, whereas CD14 played a lesser important role.…”

Section: Combined Inhibition Of Complement and Cd14mentioning

confidence: 99%

Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases—C3 or C5 emerge together with CD14 as promising targets

Barratt‐Due

Pischke

Nilsson

et al. 2016

Journal of Leukocyte Biology

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“…The inflammatory response in Gram-positive sepsis is more complement-driven compared to the Gram-negative response, which is largely LPS-dependent and therefore more TLR-4-driven [28]. Although both complement and CD14 play vital roles mediating E. coli-as well as S. aureus-induced inflammation, it is uncertain whether the anti-CD14 effects observed on the S. aureus-induced responses reflect the involvement of TLR-2, TLR-9 or other TLRs [21,29].…”

Section: Discussionmentioning

confidence: 99%

The anti-inflammatory effect of combined complement and CD14 inhibition is preserved during escalating bacterial load

Egge

Barratt‐Due

Nymo

et al. 2015

Clinical and Experimental Immunology

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SummaryCombined inhibition of complement and CD14 is known to attenuate bacterial-induced inflammation, but the dependency of the bacterial load on this effect is unknown. Thus, we investigated whether the effect of such combined inhibition on Escherichia coli-and Staphylococcus aureus-induced inflammation was preserved during increasing bacterial concentrations. Human whole blood was preincubated with anti-CD14, eculizumab (C5-inhibitor) or compstatin (C3-inhibitor), or combinations thereof. Then heat-inactivated bacteria were added at final concentrations of 5 3 10 4 21 3 10 8 /ml (E. coli) or 5 3 10 7 24 3 10 8 /ml (S. aureus). Inflammatory markers were measured using enzyme-linked immunosorbent assay (ELISA), multiplex technology and flow cytometry. Combined inhibition of complement and CD14 significantly (P < 0.05) reduced E. coli-induced interleukin (IL)-6 by 40-92% at all bacterial concentrations. IL-1b, IL-8 and macrophage inflammatory protein (MIP)-1a were significantly (P < 0.05) inhibited by 53-100%, and the effect was lost only at the highest bacterial concentration. Tumour necrosis factor (TNF) and MIP-1b were significantly (P < 0.05) reduced by 80-97% at the lowest bacterial concentration. Monocyte and granulocyte CD11b were significantly (P < 0.05) reduced by 63-91% at all bacterial doses. Lactoferrin was significantly (P < 0.05) attenuated to the level of background activity at the lowest bacterial concentration. Similar effects were observed for S. aureus, but the attenuation was, in general, less pronounced. Compared to E. coli, much higher concentrations of S. aureus were required to induce the same cytokine responses. This study demonstrates generally preserved effects of combined complement and CD14 inhibition on Gram-negative and Grampositive bacterial-induced inflammation during escalating bacterial load. The implications of these findings for future therapy of sepsis are discussed.

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Combined inhibition of complement and CD14 efficiently attenuated the inflammatory response induced by Staphylococcus aureus in a human whole blood model

Cited by 7 publications

References 0 publications

Compstatin: a C3‐targeted complement inhibitor reaching its prime for bedside intervention

Compstatin: a C3‐targeted complement inhibitor reaching its prime for bedside intervention

Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases—C3 or C5 emerge together with CD14 as promising targets

The anti-inflammatory effect of combined complement and CD14 inhibition is preserved during escalating bacterial load

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