title: Dose-response met-RANTES treatment of experimental periodontitis: a narrow edge between the disease severity attenuation and infection control.
abstract: Chemokines and chemokine receptors have been implicated in the selective migration of leukocyte subsets to periodontal tissues, which consequently influences the disease outcome. Among these chemoattractants, the chemokines CCL3, CCL4 and CCL5 and its receptors, CCR1 and CCR5, have been associated with increased disease severity in mice and humans. Therefore, in this study we investigated the modulation of experimental periodontitis outcome by the treatment with a specific antagonist of CCR1 and 5 receptors, called met-RANTES. C57Bl/6 mice was orally infected with Aggregatibacter actinomycetemcomitans and treated with 0.05, 0.1, 0.5, 1.5 and 5 mg doses of met-RANTES on alternate days, and evaluated by morphometric, cellular, enzymatic and molecular methods. At 0.5 mg up to 5 mg doses, a strong reduction in the alveolar bone loss and inflammatory cell migration were observed. Interestingly, 5 mg dose treatment resulted in the maximum inhibition of inflammatory cell migration, but resulted in a similar inhibition of bone loss when compared with the lower doses, and also resulted in increased bacterial load and CRP response. When 0.5 and 5 mg therapy regimens were compared it was observed that both therapeutic protocols were able to downregulate the levels of pro-inflammatory, Th1-type and osteoclastogenic cytokines, and CD3+ and F4/80+ cells migration to periodontal tissues, but the high dose modulates host response in a more pronounced and unspecific and excessive way, interfering also with the production of antimicrobial mediators such as MPO, iNOS and IgG, and with GR1+ and CD19+ cells migration. Our results demonstrate a thin line between beneficial immunoregulation and impaired host defense during experimental periodontitis, and the determination of the exact equilibrium point is mandatory for the improvement of immune-targeted therapy of periodontitis.
authors.affiliation: Department of Biological Sciences, School of Dentistry of Bauru, São Paulo University-FOB/USP, Bauru, Sao Paulo, Brazil.
authors.forename: Carlos Eduardo
authors.initials: CE
authors.lastname: Repeke
authors.forename: Samuel Barros
authors.initials: SB
authors.lastname: Ferreira
authors.forename: Andreia Espindola
authors.initials: AE
authors.lastname: Vieira
authors.forename: Elcia Maria
authors.initials: EM
authors.lastname: Silveira
authors.forename: Mario Julio
authors.initials: MJ
authors.lastname: Avila-Campos
authors.forename: João Santana
authors.initials: JS
authors.lastname: da Silva
authors.forename: Carlos Ferreira
authors.initials: CF
authors.lastname: Santos
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Campanelli
authors.forename: Ana Paula Favaro
authors.initials: AP
authors.lastname: Trombone
authors.forename: Gustavo Pompermaier
authors.initials: GP
authors.lastname: Garlet
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D018946:Chemokine CCL5 / Q000494:pharmacology* / Q000627:therapeutic use; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015661:Pasteurellaceae / Q000187:drug effects / Q000472:pathogenicity; D016871:Pasteurellaceae Infections / Q000188:drug therapy*; D010518:Periodontitis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents; D015415:Biomarkers; D018946:Chemokine CCL5; D016207:Cytokines; C108335:RANTES, Met-