Dataset Information

Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters.

ABSTRACT: Approximately 350,000 individuals in the United States rely on maintenance hemodialysis treatment because of end-stage renal disease. Despite improvements in dialysis technology, the mortality rate for patients treated with maintenance dialysis is still exceptionally high, with a 5-year survival rate of only 35%. Many patients succumb to conditions resulting at least in part from the chronic induction of inflammation. Among the triggers of inflammation, the complement system is of particular importance, being a well-appreciated mediator of inflammatory processes that is involved in many pathologic states. Here we used a refined pre-clinical model of hemodialysis in cynomolgus monkeys to confirm that even modern, polymer-based hemodialysis filters activate complement and to evaluate the potential of Cp40, a peptidic C3 inhibitor, to attenuate hemodialysis-induced complement activation. Our data show marked induction of complement activation even after only a single session of hemodialysis. Importantly, complete inhibition of complement activation was achieved in response to two distinct Cp40 treatment regimens. Further, we show that application of Cp40 during hemodialysis resulted in increased levels of the anti-inflammatory cytokine IL-10, indicating that Cp40 may be a potent and cost-effective treatment option for attenuating chronic inflammatory conditions in dialysis-dependent patients.

SUBMITTER: Reis ES

PROVIDER: S-EPMC4355228 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters.

Reis Edimara S ES DeAngelis Robert A RA Chen Hui H Resuello Ranillo R G RR Ricklin Daniel D Lambris John D JD

Immunobiology 20141103 4

Approximately 350,000 individuals in the United States rely on maintenance hemodialysis treatment because of end-stage renal disease. Despite improvements in dialysis technology, the mortality rate for patients treated with maintenance dialysis is still exceptionally high, with a 5-year survival rate of only 35%. Many patients succumb to conditions resulting at least in part from the chronic induction of inflammation. Among the triggers of inflammation, the complement system is of particular imp ...[more]

PMID: 25468722

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Project description:Periodontitis is a prevalent chronic inflammatory disease associated with dysbiosis. Although complement inhibition has been successfully used to treat periodontitis in animal models, studies globally analyzing inflamed tissue proteins to glean insight into possible mechanisms of action are missing. Using quantitative shotgun proteomics, we aimed to investigate differences in composition of inflammatory gingival tissue exudate ("gingival crevicular fluid"; GCF), before and after local administration of an inhibitor of the central complement component, C3, in nonhuman primates. The C3 inhibitor, Cp40 (also known as AMY-101) was administered locally in the maxillary gingival tissue of cynomolgus monkeys with established periodontitis, either once a week (1×-treatment; n = 5 animals) or three times per week (3×-treatment; n = 10 animals), for 6 weeks followed by another 6 weeks of observation in the absence of treatment. 45 GCF samples were processed for FASP digestion and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Data were processed using the ProgenesisQI software. The statistical significance of differences between the groups was determined by RM-ANOVA, and a protein expression change was considered as a true regulation at >2-fold and p < 0.05. The human orthologues were subjected to Gene Ontology analyses using PANTHER. Data are available via ProteomeXchange with identifier PXD009502. 573 proteins with >2 peptides were longitudinally quantified. Both 3× and 1× administration of Cp40 resulted in significant down-regulation of dozens of proteins during the 6-week course of treatment as compared to baseline. Following drug withdrawal at 6 weeks, more than 50% of the down-regulated proteins showed increased levels at week 12. The top scored pathway was "complement activation, alternative pathway", and several proteins involved in this pathway were down-regulated at 6 weeks. We mapped the proteomic fingerprint changes in local tissue exudate of cynomolgus monkey periodontitis in response to C3 inhibition and identified the alternative pathway of complement activation and leukocyte degranulation as main targets, which are thus likely to play significant roles in periodontal disease pathogenesis. Label-free quantitative proteomics strategies utilizing GCF are powerful tools for the identification of treatment targets and providing insights into disease mechanisms.

Dataset Information

Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters.

Publications

Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters.

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