compstatin and Disease-Models--Animal

Chronic periodontitis is induced by a dysbiotic microbiota and leads to inflammatory destruction of tooth-supporting connective tissue and bone. The third component of complement, C3, is a point of convergence of distinct complement activation mechanisms, but its involvement in periodontitis was not previously addressed. We investigated this question using two animal species models, namely, C3-deficient or wild-type mice and nonhuman primates (NHPs) locally treated with a potent C3 inhibitor (the compstatin analog Cp40) or an inactive peptide control. In mice, C3 was required for maximal periodontal inflammation and bone loss, and for the sustenance of the dysbiotic microbiota. The effect of C3 on the microbiota was therefore different from that reported for the C5a receptor, which is required for the initial induction of dysbiosis. C3-dependent bone loss was demonstrated in distinct models, including Porphyromonas gingivalis-induced periodontitis, ligature-induced periodontitis, and aging-associated periodontitis. Importantly, local treatment of NHPs with Cp40 inhibited ligature-induced periodontal inflammation and bone loss, which correlated with lower gingival crevicular fluid levels of proinflammatory mediators (e.g., IL-17 and RANKL) and decreased osteoclastogenesis in bone biopsy specimens, as compared with control treatment. To our knowledge, this is the first time, for any disease, that complement inhibition in NHPs was shown to inhibit inflammatory processes that lead to osteoclastogenesis and bone loss. These data strongly support the feasibility of C3-targeted intervention for the treatment of human periodontitis.

Topics: Animals; Bacteroidaceae Infections; Bone Resorption; Complement C3; Disease Models, Animal; Female; Humans; Inflammation Mediators; Macaca fascicularis; Male; Mice; Osteoclasts; Peptides, Cyclic; Periodontitis; Porphyromonas gingivalis; Pyridones

Severe sepsis leads to massive activation of coagulation and complement cascades that could contribute to multiple organ failure and death. To investigate the role of the complement and its crosstalk with the hemostatic system in the pathophysiology and therapeutics of sepsis, we have used a potent inhibitor (compstatin) administered early or late after Escherichia coli challenge in a baboon model of sepsis-induced multiple organ failure. Compstatin infusion inhibited sepsis-induced blood and tissue biomarkers of complement activation, reduced leucopenia and thrombocytopenia, and lowered the accumulation of macrophages and platelets in organs. Compstatin decreased the coagulopathic response by down-regulating tissue factor and PAI-1, diminished global blood coagulation markers (fibrinogen, fibrin-degradation products, APTT), and preserved the endothelial anticoagulant properties. Compstatin treatment also improved cardiac function and the biochemical markers of kidney and liver damage. Histologic analysis of vital organs collected from animals euthanized after 24 hours showed decreased microvascular thrombosis, improved vascular barrier function, and less leukocyte infiltration and cell death, all consistent with attenuated organ injury. We conclude that complement-coagulation interplay contributes to the progression of severe sepsis and blocking the harmful effects of complement activation products, especially during the organ failure stage of severe sepsis is a potentially important therapeutic strategy.

Topics: Animals; Biomarkers; Blood Coagulation; Blood Pressure; Complement Activation; Complement Inactivator Proteins; Cytokines; Disease Models, Animal; Escherichia coli Infections; Multiple Organ Failure; Papio; Peptides, Cyclic; Sepsis

For the past 10 years, number of evidence has shown that activation of complement cascade has been associated with age-related macular degeneration (AMD). The genome wide association study in American population with dominantly dry-type AMD has revealed strong association with single nucleotide polymorphism (SNP) of complement genes. Protein composition of drusen, a deposit observed in sub-retinal space between Bruch's membrane and retinal pigment epithelial (RPE), contains active complement molecules in human and monkey. These evidences have leaded us to consider the possibility of suppressing complement cascade in the retina to delay or reverse the onset of AMD. To test is hypothesis we used the C3 inhibitor Compstatin on primate model with early-onset macular degeneration which develop drusen in less than 2 years after birth. Our preliminary result showed drusen disappearance after 6 months of intravitreal injection.

Topics: Age of Onset; Animals; Complement C3; Complement System Proteins; Disease Models, Animal; Humans; Intravitreal Injections; Macaca fascicularis; Macular Degeneration; Peptides, Cyclic; Retinal Drusen