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. 2016 Mar;43(3):238-49.
doi: 10.1111/jcpe.12507. Epub 2016 Mar 3.

"VSports注册入口" Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3

Tomoki Maekawa  1   2 , Ruel A Briones  3 , Ranillo R G Resuello  4 , Joel V Tuplano  4 , Evlambia Hajishengallis  5 , Tetsuhiro Kajikawa  1 , Sophia Koutsogiannaki  6 , Cristina A G Garcia  3 , Daniel Ricklin  6 , John D Lambris  6 , George Hajishengallis  1
Affiliations

Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3

Tomoki Maekawa (V体育官网) et al. J Clin Periodontol. 2016 Mar.

"VSports app下载" Abstract

Aim: Human periodontitis is associated with overactivation of complement, which is triggered by different mechanisms converging on C3, the central hub of the system VSports手机版. We assessed whether the C3 inhibitor Cp40 inhibits naturally occurring periodontitis in non-human primates (NHPs). .

Materials and methods: Non-human primates with chronic periodontitis were intra-gingivally injected with Cp40 either once (5 animals) or three times (10 animals) weekly for 6 weeks followed by a 6-week follow-up period. Clinical periodontal examinations and collection of gingival crevicular fluid and biopsies of gingiva and bone were performed at baseline and during the study. A one-way repeated-measures anova was used for data analysis. V体育安卓版.

Results: Whether administered once or three times weekly, Cp40 caused a significant reduction in clinical indices that measure periodontal inflammation (gingival index and bleeding on probing), tissue destruction (probing pocket depth and clinical attachment level) or tooth mobility. These clinical changes were associated with significantly reduced levels of pro-inflammatory mediators and decreased numbers of osteoclasts in bone biopsies. The protective effects of Cp40 persisted, albeit at reduced efficacy, for at least 6 weeks following drug discontinuation V体育ios版. .

Conclusion: Cp40 inhibits pre-existing chronic periodontal inflammation and osteoclastogenesis in NHPs, suggesting a novel adjunctive anti-inflammatory therapy for treating human periodontitis. VSports最新版本.

Keywords: complement; compstatin; cytokines; inflammation; non-human primates; periodontitis. V体育平台登录.

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Conflict of interest statement

Conflict of interest and source of funding statement

G. H. and J. D. L. have a joint patent application that describes the use of complement inhibitors for therapeutic purposes in periodontitis. J. D. L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors for clinical applications. This work was supported by grants from the National Institutes of Health (AI068730 and AI030040 to J. D VSports在线直播. L. ; DE015254, DE017138, DE021685, and DE024716 to G. H. ) and the European Commission (FP7-DIREKT 602699 to J. D. L. ).

Figures (VSports app下载)

Figure 1
Figure 1. Cp40 decreases inflammatory clinical parameters of naturally occurring chronic periodontitis in NHPs after local administration three times weekly
Cp40 was injected – three times weekly for 6 weeks – into the interdental papillae and the distal gingiva of the second molars of the maxilla (“Cp40”), whereas the mandible was not treated (“Untreated”). Each animal was clinically examined at the indicated time points and the following clinical parameters were recorded: (A) gingival index; (B) bleeding on probing; (C) probing pocket depth; (D) clinical attachment level; (E) mobility index; and (F) plaque index. The data were expressed relative to the baseline values (at week 0), set as 100 (Raw data are shown for each animal in supplementary figures S1 to S10). Results are means ± SD (n =10 monkeys). *P < 0.05 and **P < 0.01 compared to baseline (one-way repeated-measures ANOVA and Bonferroni’s multiple comparisons test).
Figure 2
Figure 2. Single weekly administration of Cp40 decreases inflammatory clinical parameters of naturally occurring chronic periodontitis in NHPs
Cp40 was injected – once weekly for 6 weeks – into the interdental papillae and the distal gingiva of the second molars of the maxilla (“Cp40”), whereas the mandible was not treated (“Untreated”). Each animal was clinically examined at the indicated time points and the following clinical parameters were recorded: (A) gingival index; (B) bleeding on probing; (C) probing pocket depth; (D) clinical attachment level; (E) mobility index; and (F) plaque index. The data were expressed relative to the baseline values (at week 0), set as 100 (Raw data are shown for each animal in supplementary figures S12 to S16). Results are means ± SD (n = 5 monkeys). *P < 0.05 and **P < 0.01 compared to baseline (one-way repeated-measures ANOVA and Bonferroni’s multiple comparisons test).
Figure 3
Figure 3. Decreased GCF levels of pro-inflammatory and pro-osteoclastogenic mediators in NHPs with natural periodontitis after local treatment with Cp40 three times weekly
At the indicated time-points, GCF was collected from monkeys with natural periodontitis which were treated three times weekly for 6 weeks with Cp40 in the maxilla (“Cp40”) but not in the mandible (“Untreated”). Total cytokine or mediator content (A, IL-1β; B, IL-6; C, IL-8; D, IL-17; E, RANKL; F, OPG; G, C3a; H, C5/C5a) in the eluted GCF samples was measured using a Bio-Plex system or ELISA (C3a only). Data are means ± SD (n = 10 monkeys). *P < 0.05; **P < 0.01 compared to baseline (one-way repeated-measures ANOVA and Bonferroni’s multiple comparisons test).
Figure 4
Figure 4. Single weekly administration of Cp40 decreases the levels of pro-inflammatory and pro-osteoclastogenic mediators in the GCF of NHPs with natural periodontitis
At the indicated time-points, GCF was collected from monkeys with natural periodontitis which were treated once weekly for 6 weeks with Cp40 in the maxilla (“Cp40”) but not in the mandible (“Untreated”). Total cytokine or mediator content (A, IL-1β; B, IL-6; C, IL-8; D, IL-17; E, RANKL; F, OPG; G, C3a; H, C5/C5a) in the eluted GCF samples was measured using a Bio-Plex system or ELISA (C3a only). Data are means ± SD (n = 5 monkeys). *P < 0.05; **P < 0.01 compared to baseline (one-way repeated-measures ANOVA and Bonferroni’s multiple comparisons test).
Figure 5
Figure 5. Expression of inflammatory and osteoclastogenesis-related molecules in periodontal biopsy specimens from Cp40-treated NHPs
Periodontal biopsy specimens from the maxillae of NHPs treated with Cp40 were processed for fluorescent microscopy. The specimens were taken before (week 0) and after (week 6) treatment with Cp40 locally administered three times weekly. Shown are representative overlays of differential interference contrast (DIC) and fluorescent images stained for the indicated molecules. B, bone; CT, connective tissue. Scale bar, 100 μm.
Figure 6
Figure 6. Cp40 inhibits mRNA expression of gingival inflammatory mediators in NHPs
Gingival tissue biopsies were taken from the maxilla of NHPs treated three times (A) or once (B) weekly for 6 weeks and extracted RNA was subjected to real-time PCR processed to determine mRNA expression of the indicated molecules at the indicated times. Data were normalized to GADPH mRNA and are presented as fold change in the transcript levels relative to baseline levels (prior to treatment; week 0), set as 1. Data are means ± SD (A, n = 10 monkeys; B, n = 5 monkeys). *P < 0.05; **P < 0.01 compared to baseline (one-way repeated-measures ANOVA and Bonferroni’s multiple comparisons test). NS, not significant.
Figure 7
Figure 7. Decreased numbers of osteoclasts after treatment of natural NHP periodontitis with Cp40
At the indicated time-points, alveolar bone biopsies were obtained from monkeys with natural periodontitis. The animals were treated three times (A) or once (B) weekly for 6 weeks with Cp40 in the maxilla but not in the mandible (“Untreated”). TRAP-positive multinucleated cells (osteoclasts) were enumerated in 10 randomly selected sections for each bone biopsy specimen from the maxilla or mandible of each of the animals. The numbers of osteoclasts were averaged for each biopsy specimen and are represented by dots. Scatter dot plots with mean ± SD are shown for each group of monkeys (A, n = 10; B, n = 5 animals). Indicated P values determined by one-way repeated-measures ANOVA and Tukey’s multiple comparisons test.
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References

    1. Abe T, Hosur KB, Hajishengallis E, Reis ES, Ricklin D, Lambris JD, Hajishengallis G. Local complement-targeted intervention in periodontitis: proof-of-concept using a C5a receptor (CD88) antagonist. J Immunol. 2012;189:5442–5448. - PMC (V体育2025版) - PubMed
    1. Abe T, Shin J, Hosur K, Udey MC, Chavakis T, Hajishengallis G. Regulation of osteoclast homeostasis and inflammatory bone loss by MFG-E8. J Immunol. 2014;193:1383–1391. - "V体育安卓版" PMC - PubMed
    1. Abusleme L, Dupuy AK, Dutzan N, Silva N, Burleson JA, Strausbaugh LD, Gamonal J, Diaz PI. The subgingival microbiome in health and periodontitis and its relationship with community biomass and inflammation. ISME J. 2013;7:1016–1025. - PMC - PubMed
    1. Armitage GC. Classifying periodontal diseases: a long-standing dilemma. Periodontol 2000. 2002;30:9–23. - PubMed
    1. Asgari E, Le Friec G, Yamamoto H, Perucha E, Sacks SS, Kohl J, Cook HT, Kemper C. C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood. 2013;122:3473–3481. - "VSports最新版本" PubMed

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