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

Journal of Clinical Periodontology

Volumn 43, Issue 3, 2016, Pages 238-249

  Maekawa, Tomoki ^a,b   Briones, Ruel A ^c   Resuello, Ranillo R G ^d   Tuplano, Joel V ^d   Hajishengallis, Evlambia ^a   Kajikawa, Tetsuhiro ^a   Koutsogiannaki, Sophia ^e   Garcia, Cristina A G ^c   Ricklin, Daniel ^e   Lambris, John D ^e   Hajishengallis, George ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b NIIGATA UNIVERSITY GRADUATE SCHOOL OF MEDICAL AND DENTAL SCIENCES   (Japan)

^c Manila Central University   (Philippines)

^d Simian Conservation Breeding and Research Center (SICONBREC)   (Philippines)

^e UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

complement; compstatin; cytokines; inflammation; non human primates; periodontitis

Indexed keywords

COMPLEMENT COMPONENT C3; PEPTIDE;

ANIMAL; GINGIVITIS; MACACA FASCICULARIS; MALE; PERIODONTAL ATTACHMENT LOSS; PERIODONTAL INDEX; PERIODONTAL POCKET; PERIODONTITIS;

ANIMALS; COMPLEMENT C3; GINGIVAL CREVICULAR FLUID; MACACA FASCICULARIS; MALE; PEPTIDES; PERIODONTAL ATTACHMENT LOSS; PERIODONTAL INDEX; PERIODONTAL POCKET; PERIODONTITIS;

EID: 84960146246     PISSN: 03036979     EISSN: 1600051X     Source Type: Journal    
DOI: 10.1111/jcpe.12507     Document Type: Article

References (87)

1. Abe, T., Hosur, K. B., Hajishengallis, E., Reis, E. S., Ricklin, D., Lambris, J. D., &, Hajishengallis, G., (2012) Local complement-targeted intervention in periodontitis: proof-of-concept using a C5a receptor (CD88) antagonist. Journal of Immunology 189, 5442-5448.
2. Abe, T., Shin, J., Hosur, K., Udey, M. C., Chavakis, T., &, Hajishengallis, G., (2014) Regulation of osteoclast homeostasis and inflammatory bone loss by MFG-E8. Journal of Immunology 193, 1383-1391.
3. Abusleme, L., Dupuy, A. K., Dutzan, N., Silva, N., Burleson, J. A., Strausbaugh, L. D., Gamonal, J., &, Diaz, P. I., (2013) The subgingival microbiome in health and periodontitis and its relationship with community biomass and inflammation. ISME Journal 7, 1016-1025.
4. Armitage, G. C., (2002) Classifying periodontal diseases: a long-standing dilemma. Periodontology 2000 30, 9-23.
5. Asgari, E., Le Friec, G., Yamamoto, H., Perucha, E., Sacks, S. S., Kohl, J., Cook, H. T., &, Kemper, C., (2013) C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood 122, 3473-3481.
6. Assuma, R., Oates, T., Cochran, D., Amar, S., &, Graves, D. T., (1998) IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. Journal of Immunology 160, 403-409.
7. Attstrom, R., Laurel, A. B., Lahsson, U., &, Sjoholm, A., (1975) Complement factors in gingival crevice material from healthy and inflamed gingiva in humans. Journal of Periodontal Research 10, 19-27.
8. Beikler, T., &, Flemmig, T. F., (2011) Oral biofilm-associated diseases: trends and implications for quality of life, systemic health and expenditures. Periodontology 2000 55, 87-103.
9. Belibasakis, G. N., &, Bostanci, N., (2012) The RANKL-OPG system in clinical periodontology. Journal of Clinical Periodontology 39, 239-248.
10. Boespflug, N. D., Kumar, S., McAlees, J. W., Phelan, J. D., Grimes, H. L., Hoebe, K., Hai, T., Filippi, M. D., &, Karp, C. L., (2014) ATF3 is a novel regulator of mouse neutrophil migration. Blood 123, 2084-2093.
11. Bostanci, N., Emingil, G., Saygan, B., Turkoglu, O., Atilla, G., Curtis, M. A., &, Belibasakis, G. N., (2009) Expression and regulation of the NALP3 inflammasome complex in periodontal diseases. Clinical and Experimental Immunology 157, 415-422.
12. Bostanci, N., Ilgenli, T., Emingil, G., Afacan, B., Han, B., Toz, H., Atilla, G., Hughes, F. J., &, Belibasakis, G. N., (2007) Gingival crevicular fluid levels of RANKL and OPG in periodontal diseases: implications of their relative ratio. Journal of Clinical Periodontology 34, 370-376.
13. Brecx, M. C., Nalbandian, J., Ooya, K., Kornman, K. S., &, Robertson, P. B., (1985) Morphological studies on periodontal disease in the cynomolgus monkey. II. Light microscopic observations on ligature-induced periodontitis. Journal of Periodontal Research 20, 165-175.
14. Breivik, T., Gundersen, Y., Gjermo, P., Taylor, S. M., Woodruff, T. M., &, Opstad, P. K., (2011) Oral treatment with complement factor C5a receptor (CD88) antagonists inhibits experimental periodontitis in rats. Journal of Periodontal Research 46, 643-647.
15. Cappelli, D., Holt, S. C., Singer, R. E., Pickrum, H. M., &, Ebersole, J. L., (2000) Effects of 0.12% chlorhexidine gluconate on experimental gingivitis in non-human primates: clinical and microbiological alterations. Oral Diseases 6, 124-131.
16. Chapple, I. L., (2014) Time to take periodontitis seriously. BMJ 348, g2645.
17. Colombo, A. P., Bennet, S., Cotton, S. L., Goodson, J. M., Kent, R., Haffajee, A. D., Socransky, S. S., Hasturk, H., Van Dyke, T. E., Dewhirst, F. E., &, Paster, B. J., (2012) Impact of periodontal therapy on the subgingival microbiota of severe periodontitis: comparison between good responders and individuals with refractory periodontitis using the human oral microbe identification microarray. Journal of Periodontology 83, 1279-1287.
18. Courts, F. J., Boackle, R. J., Fudenberg, H. H., &, Silverman, M. S., (1977) Detection of functional complement components in gingival crevicular fluid from humans with periodontal diseases. Journal of Dental Research 56, 327-331.
19. Demmer, R. T., &, Papapanou, P. N., (2010) Epidemiologic patterns of chronic and aggressive periodontitis. Periodontology 2000 53, 28-44.
20. Devi, S., Li, A., Westhorpe, C. L., Lo, C. Y., Abeynaike, L. D., Snelgrove, S. L., Hall, P., Ooi, J. D., Sobey, C. G., Kitching, A. R., &, Hickey, M. J., (2013) Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus. Nature Medicine 19, 107-112.
21. Ebersole, J. L., Cappelli, D., Mathys, E. C., Steffen, M. J., Singer, R. E., Montgomery, M., Mott, G. E., &, Novak, M. J., (2002) Periodontitis in humans and non-human primates: oral-systemic linkage inducing acute phase proteins. Annals of Periodontology 7, 102-111.
22. Ebersole, J. L., Kirakodu, S., Novak, M. J., Exposto, C. R., Stromberg, A. J., Shen, S., Orraca, L., Gonzalez-Martinez, J., &, Gonzalez, O. A., (2015) Effects of aging in the expression of NOD-like receptors and inflammasome-related genes in oral mucosa. Molecular Oral Microbiology. doi: 10.1111/omi.12121. [Epub ahead of print].
23. Ebersole, J. L., Kirakodu, S., Novak, M. J., Stromberg, A. J., Shen, S., Orraca, L., Gonzalez-Martinez, J., Burgos, A., &, Gonzalez, O. A., (2014) Cytokine gene expression profiles during initiation, progression and resolution of periodontitis. Journal of Clinical Periodontology 41, 853-861.
24. Eke, P. I., Dye, B. A., Wei, L., Slade, G. D., Thornton-Evans, G. O., Borgnakke, W. S., Taylor, G. W., Page, R. C., Beck, J. D., &, Genco, R. J., (2015) Update on prevalence of periodontitis in adults in the United States: NHANES 2009 to 2012. Journal of Periodontology 86, 611-622.
25. Eke, P. I., Dye, B. A., Wei, L., Thornton-Evans, G. O., &, Genco, R. J., (2012) Prevalence of periodontitis in adults in the United States: 2009 and 2010. Journal of Dental Research 91, 914-920.
26. Eskan, M. A., Jotwani, R., Abe, T., Chmelar, J., Lim, J. H., Liang, S., Ciero, P. A., Krauss, J. L., Li, F., Rauner, M., Hofbauer, L. C., Choi, E. Y., Chung, K. J., Hashim, A., Curtis, M. A., Chavakis, T., &, Hajishengallis, G., (2012) The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nature Immunology 13, 465-473.
27. Genco, R. J., &, Genco, F. D., (2014) Common risk factors in the management of periodontal and associated systemic diseases: the dental setting and interprofessional collaboration. Journal of Evidence-Based Dental Practice 14 (Suppl), 4-16.
28. Gonzalez, O. A., Nagarajan, R., Novak, M. J., Orraca, L., Gonzalez-Martinez, J. A., Kirakodu, S. S., &, Ebersole, J. L., (2015) Immune system transcriptome in gingival tissues of young nonhuman primates. Journal of Periodontal Research 41, 952-957.
29. Graves, D., (2008) Cytokines that promote periodontal tissue destruction. Journal of Periodontology 79, 1585-1591.
30. Hajishengallis, G., (2010) Complement and periodontitis. Biochemical Pharmacology 80, 1992-2001.
31. Hajishengallis, G., (2014a) Aging and its impact on innate immunity and inflammation: implications for periodontitis. Journal of Oral Biosciences 56, 30-37.
32. Hajishengallis, G., (2014b) The inflammophilic character of the periodontitis-associated microbiota. Molecular Oral Microbiology 29, 248-257.
33. Hajishengallis, G., (2015) Periodontitis: from microbial immune subversion to systemic inflammation. Nature Reviews. Immunology 15, 30-44.
34. Hajishengallis, G., &, Lambris, J. D., (2010) Crosstalk pathways between toll-like receptors and the complement system. Trends in Immunology 31, 154-163.
35. Hajishengallis, G., Liang, S., Payne, M. A., Hashim, A., Jotwani, R., Eskan, M. A., McIntosh, M. L., Alsam, A., Kirkwood, K. L., Lambris, J. D., Darveau, R. P., &, Curtis, M. A., (2011) Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host & Microbe 10, 497-506.
36. Han, Y. W., Houcken, W., Loos, B. G., Schenkein, H. A., &, Tezal, M., (2014) Periodontal disease, atherosclerosis, adverse pregnancy outcomes, and head-and-neck cancer. Advances in Dental Research 26, 47-55.
37. Hasturk, H., Kantarci, A., Goguet-Surmenian, E., Blackwood, A., Andry, C., Serhan, C. N., &, Van Dyke, T. E., (2007) Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo. Journal of Immunology 179, 7021-7029.
38. Heitz-Mayfield, L. J., (2005) Disease progression: identification of high-risk groups and individuals for periodontitis. Journal of Clinical Periodontology 32 (Suppl 6), 196-209.
39. Kebschull, M., Demmer, R. T., &, Papapanou, P. N., (2010) "Gum bug leave my heart alone": epidemiologic and mechanistic evidence linking periodontal infections and atherosclerosis. Journal of Dental Research 89, 879-902.
40. Kirjavainen, V., Jarva, H., Biedzka-Sarek, M., Blom, A. M., Skurnik, M., &, Meri, S., (2008) Yersinia enterocolitica serum resistance proteins YadA and ail bind the complement regulator C4b-binding protein. PLoS Pathogens 4, e1000140.
41. Kornman, K. S., Holt, S. C., &, Robertson, P. B., (1981) The microbiology of ligature-induced periodontitis in the cynomolgus monkey. Journal of Periodontal Research 16, 363-371.
42. Koziel, J., Mydel, P., &, Potempa, J., (2014) The link between periodontal disease and rheumatoid arthritis: an updated review. Current Rheumatology Reports 16, 408.
43. Lalla, E., &, Papapanou, P. N., (2011) Diabetes mellitus and periodontitis: a tale of two common interrelated diseases. Nature Reviews. Endocrinology 7, 738-748.
44. Lally, E. T., McArthur, W. P., &, Baehni, P. C., (1982) Biosynthesis of complement components in chronically inflamed gingiva. Journal of Periodontal Research 17, 257-262.
45. Lamkanfi, M., &, Dixit, V. M., (2014) Mechanisms and functions of inflammasomes. Cell 157, 1013-1022.
46. Lamont, R. J., &, Hajishengallis, G., (2015) Polymicrobial synergy and dysbiosis in inflammatory disease. Trends in Molecular Medicine 21, 172-183.
47. Lee, S. K., &, Lorenzo, J. A., (1999) Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinology 140, 3552-3561.
48. Li, K. L., Vogel, R., Jeffcoat, M. K., Alfano, M. C., Smith, M. A., Collins, J. G., &, Offenbacher, S., (1996) The effect of ketoprofen creams on periodontal disease in rhesus monkeys. Journal of Periodontal Research 31, 525-532.
49. Liang, S., Krauss, J. L., Domon, H., McIntosh, M. L., Hosur, K. B., Qu, H., Li, F., Tzekou, A., Lambris, J. D., &, Hajishengallis, G., (2011) The C5a receptor impairs IL-12-dependent clearance of Porphyromonas gingivalis and is required for induction of periodontal bone loss. Journal of Immunology 186, 869-877.
50. Maekawa, T., Abe, T., Hajishengallis, E., Hosur, K. B., DeAngelis, R. A., Ricklin, D., Lambris, J. D., &, Hajishengallis, G., (2014a) Genetic and intervention studies implicating complement C3 as a major target for the treatment of periodontitis. Journal of Immunology 192, 6020-6027.
51. Maekawa, T., Krauss, J. L., Abe, T., Jotwani, R., Triantafilou, M., Triantafilou, K., Hashim, A., Hoch, S., Curtis, M. A., Nussbaum, G., Lambris, J. D., &, Hajishengallis, G., (2014b) Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host & Microbe 15, 768-778.
52. Marsh, P. D., (2003) Are dental diseases examples of ecological catastrophes? Microbiology 149, 279-294.
53. Mastellos, D. C., Ricklin, D., Hajishengallis, E., Hajishengallis, G., &, Lambris, J. D., (2015a) Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention. Molecular Oral Microbiology. doi: 10.1111/omi.12129. [Epub ahead of print].
54. Mastellos, D. C., Yancopoulou, D., Kokkinos, P., Huber-Lang, M., Hajishengallis, G., Biglarnia, A. R., Lupu, F., Nilsson, B., Risitano, A. M., Ricklin, D., &, Lambris, J. D., (2015b) Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention. European Journal of Clinical Investigation 45, 423-440.
55. Miossec, P., &, Kolls, J. K., (2012) Targeting IL-17 and TH17 cells in chronic inflammation. Nature Reviews. Drug Discovery 11, 763-776.
56. Miyake, K., (2007) Innate immune sensing of pathogens and danger signals by cell surface toll-like receptors. Seminars in Immunology 19, 3-10.
57. Moritz, A. J., Cappelli, D., Lantz, M. S., Holt, S. C., &, Ebersole, J. L., (1998) Immunization with Porphyromonas gingivalis cysteine protease: effects on experimental gingivitis and ligature-induced periodontitis in Macaca fascicularis. Journal of Periodontology 69, 686-697.
58. Moutsopoulos, N. M., Kling, H. M., Angelov, N., Jin, W., Palmer, R. J., Nares, S., Osorio, M., &, Wahl, S. M., (2012) Porphyromonas gingivalis promotes Th17 inducing pathways in chronic periodontitis. Journal of Autoimmunity 39, 294-303.
59. Moutsopoulos, N. M., Konkel, J., Sarmadi, M., Eskan, M. A., Wild, T., Dutzan, N., Abusleme, L., Zenobia, C., Hosur, K. B., Abe, T., Uzel, G., Chen, W., Chavakis, T., Holland, S. M., &, Hajishengallis, G., (2014) Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss. Science Translational Medicine 6, 229ra40.
60. Niekrash, C. E., &, Patters, M. R., (1985) Simultaneous assessment of complement components C3, C4, and B and their cleavage products in human gingival fluid. II. Longitudinal changes during periodontal therapy. Journal of Periodontal Research 20, 268-275.
61. Niekrash, C. E., &, Patters, M. R., (1986) Assessment of complement cleavage in gingival fluid in humans with and without periodontal disease. Journal of Periodontal Research 21, 233-242.
62. Nikolopoulou-Papaconstantinou, A. A., Johannessen, A. C., &, Kristoffersen, T., (1987) Deposits of immunoglobulins, complement, and immune complexes in inflamed human gingiva. Acta Odontologica Scandinavica 45, 187-193.
63. Nisengard, R., Blann, D., Zelonis, L., McHenry, K., Reynolds, H., &, Zambon, J., (1989) Effects of immunization with B. macacae on induced periodontitis-preliminary findings. Immunological Investigations 18, 225-237.
64. Offenbacher, S., Braswell, L. D., Loos, A. S., Johnson, H. G., Hall, C. M., McClure, H., Orkin, J. L., Strobert, E. A., Green, M. D., &, Odle, B. M., (1987) Effects of flurbiprofen on the progression of periodontitis in Macaca mulatta. Journal of Periodontal Research 22, 473-481.
65. Page, R. C., Lantz, M. S., Darveau, R., Jeffcoat, M., Mancl, L., Houston, L., Braham, P., &, Persson, G. R., (2007) Immunization of Macaca fascicularis against experimental periodontitis using a vaccine containing cysteine proteases purified from Porphyromonas gingivalis. Oral Microbiology and Immunology 22, 162-168.
66. Page, R. C., &, Schroeder, H. E., (1982) Periodontitis in man and other animals-a comparative review. Basel, Switzerland: Karger.
67. Patters, M. R., Niekrash, C. E., &, Lang, N. P., (1989) Assessment of complement cleavage in gingival fluid during experimental gingivitis in man. Journal of Clinical Periodontology 16, 33-37.
68. Persson, G. R., Engel, D., Whitney, C., Darveau, R., Weinberg, A., Brunsvold, M., &, Page, R. C., (1994) Immunization against Porphyromonas gingivalis inhibits progression of experimental periodontitis in nonhuman primates. Infection and Immunity 62, 1026-1031.
69. Pierce, A., &, Lindskog, S., (1987) The effect of an antibiotic/corticosteroid paste on inflammatory root resorption in vivo. Oral Surgery, Oral Medicine, and Oral Pathology 64, 216-220.
70. Qu, H., Ricklin, D., Bai, H., Chen, H., Reis, E. S., Maciejewski, M., Tzekou, A., DeAngelis, R. A., Resuello, R. R., Lupu, F., Barlow, P. N., &, Lambris, J. D., (2013) New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties. Immunobiology 218, 496-505.
71. Rams, T. E., Degener, J. E., &, van Winkelhoff, A. J., (2014) Antibiotic resistance in human chronic periodontitis microbiota. Journal of Periodontology 85, 160-169.
72. Rautemaa, R., &, Meri, S., (1996) Protection of gingival epithelium against complement-mediated damage by strong expression of the membrane attack complex inhibitor protectin (CD59). Journal of Dental Research 75, 568-574.
73. Ricklin, D., Hajishengallis, G., Yang, K., &, Lambris, J. D., (2010) Complement: a key system for immune surveillance and homeostasis. Nature Immunology 11, 785-797.
74. Ricklin, D., &, Lambris, J. D., (2013) Complement in immune and inflammatory disorders: therapeutic interventions. Journal of Immunology 190, 3839-3847.
75. Risitano, A. M., Ricklin, D., Huang, Y., Reis, E. S., Chen, H., Ricci, P., Lin, Z., Pascariello, C., Raia, M., Sica, M., Del Vecchio, L., Pane, F., Lupu, F., Notaro, R., Resuello, R. R., DeAngelis, R. A., &, Lambris, J. D., (2014) Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 123, 2094-2101.
76. Roberts, F. A., Houston, L. S., Lukehart, S. A., Mancl, L. A., Persson, G. R., &, Page, R. C., (2004) Periodontitis vaccine decreases local prostaglandin E2 levels in a primate model. Infection and Immunity 72, 1166-1168.
77. Schaefer, L., (2010) Extracellular matrix molecules: endogenous danger signals as new drug targets in kidney diseases. Current Opinion in Pharmacology 10, 185-190.
78. Schenkein, H. A., &, Genco, R. J., (1977) Gingival fluid and serum in periodontal diseases. II. Evidence for cleavage of complement components C3, C3 proactivator (factor B) and C4 in gingival fluid. Journal of Periodontology 48, 778-784.
79. Shin, J., Maekawa, T., Abe, T., Hajishengallis, E., Hosur, K., Pyaram, K., Mitroulis, I., Chavakis, T., &, Hajishengallis, G., (2015) DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates. Science Translational Medicine 7, 307ra155.
80. Tonetti, M. S., D'Aiuto, F., Nibali, L., Donald, A., Storry, C., Parkar, M., Suvan, J., Hingorani, A. D., Vallance, P., &, Deanfield, J., (2007) Treatment of periodontitis and endothelial function. New England Journal of Medicine 356, 911-920.
81. Toto, P. D., Lin, L., &, Gargiulo, A., (1978) Identification of C3a, IgG, IgM in inflamed human gingiva. Journal of Dental Research 57, 696.
82. Triantafilou, K., Hughes, T. R., Triantafilou, M., &, Morgan, B. P., (2013) The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. Journal of Cell Science 126, 2903-2913.
83. White, D. A., Tsakos, G., Pitts, N. B., Fuller, E., Douglas, G. V., Murray, J. J., &, Steele, J. G., (2012) Adult Dental Health Survey 2009: common oral health conditions and their impact on the population. British Dental Journal 213, 567-572.
84. Zenobia, C., &, Hajishengallis, G., (2015) Basic biology and role of interleukin-17 in immunity and inflammation. Periodontology 2000 69, 142-159.
85. Zhan, Y., Zhang, R., Lv, H., Song, X., Xu, X., Chai, L., Lv, W., Shang, Z., Jiang, Y., &, Zhang, R., (2014) Prioritization of candidate genes for periodontitis using multiple computational tools. Journal of Periodontology 85, 1059-1069.
86. Zhang, X., Kimura, Y., Fang, C., Zhou, L., Sfyroera, G., Lambris, J. D., Wetsel, R. A., Miwa, T., &, Song, W. C., (2007) Regulation of toll-like receptor-mediated inflammatory response by complement in vivo. Blood 110, 228-236.
87. Zou, L., Feng, Y., Li, Y., Zhang, M., Chen, C., Cai, J., Gong, Y., Wang, L., Thurman, J. M., Wu, X., Atkinson, J. P., &, Chao, W., (2013) Complement factor B is the downstream effector of TLRs and plays an important role in a mouse model of severe sepsis. Journal of Immunology 191, 5625-5635.