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Dose-response met-RANTES treatment of experimental periodontitis: a narrow edge between the disease severity attenuation and infection control.

Repeke CE, Ferreira SB, Vieira AE, Silveira EM, Avila-Campos MJ, da Silva JS, Santos CF, Campanelli AP, Trombone AP, Garlet GP - PLoS ONE (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, School of Dentistry of Bauru, São Paulo University-FOB/USP, Bauru, Sao Paulo, Brazil.

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.

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Phenotypic analysis of leukocytes migration interference by distinct doses of met-RANTES treatment.C57Bl/6 mice were infected orally with AA, treated with met-RANTES at 0.5 and 5 mg doses or (V) veicule and (-) non treated, sacrificed at day 30 post-infection and evaluated for relative number of: A) F4/80+; B) CD3+; C) Gr1+; and D) CD19+ cells in periodontal tissues of WT non-treated versus vehicle, 0.5 mg and 5 mg met-RANTES treated mice by flow cytometry, all performed as described in Material and methods. Results demonstrate the relative number of cells in % when compared with untreated group. Different italic low case letters represent statistically significant differences among the doses in the same experimental group (P<0.05; One-way ANOVA), statistical analysis performed with raw data before % conversion.
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pone-0022526-g002: Phenotypic analysis of leukocytes migration interference by distinct doses of met-RANTES treatment.C57Bl/6 mice were infected orally with AA, treated with met-RANTES at 0.5 and 5 mg doses or (V) veicule and (-) non treated, sacrificed at day 30 post-infection and evaluated for relative number of: A) F4/80+; B) CD3+; C) Gr1+; and D) CD19+ cells in periodontal tissues of WT non-treated versus vehicle, 0.5 mg and 5 mg met-RANTES treated mice by flow cytometry, all performed as described in Material and methods. Results demonstrate the relative number of cells in % when compared with untreated group. Different italic low case letters represent statistically significant differences among the doses in the same experimental group (P<0.05; One-way ANOVA), statistical analysis performed with raw data before % conversion.

Mentions: In order to determine the mechanisms underlying the differential response to 0.5 and 5 mg met-RANTES doses, we initially investigated the interference of the distinct doses in the migration of F4/80+, CD3+, Gr1+ and CD19+ cells (Fig. 2). The 0.5 mg dose resulted in a significant reduction in the relative number of F4/80+ and CD3+ cells, while no differences was observed in the reduction of relative number of Gr1+ and CD19+ cells when compared with non-treated and vehicle-treated mice. Differently, the 5 mg met-RANTES protocol reduced the relative % of F4/80+, CD3+, Gr1+ and CD19+ cells in the periodontal tissues when compared with 0.5 mg of MetRANTES.


Dose-response met-RANTES treatment of experimental periodontitis: a narrow edge between the disease severity attenuation and infection control.

Repeke CE, Ferreira SB, Vieira AE, Silveira EM, Avila-Campos MJ, da Silva JS, Santos CF, Campanelli AP, Trombone AP, Garlet GP - PLoS ONE (2011)

Phenotypic analysis of leukocytes migration interference by distinct doses of met-RANTES treatment.C57Bl/6 mice were infected orally with AA, treated with met-RANTES at 0.5 and 5 mg doses or (V) veicule and (-) non treated, sacrificed at day 30 post-infection and evaluated for relative number of: A) F4/80+; B) CD3+; C) Gr1+; and D) CD19+ cells in periodontal tissues of WT non-treated versus vehicle, 0.5 mg and 5 mg met-RANTES treated mice by flow cytometry, all performed as described in Material and methods. Results demonstrate the relative number of cells in % when compared with untreated group. Different italic low case letters represent statistically significant differences among the doses in the same experimental group (P<0.05; One-way ANOVA), statistical analysis performed with raw data before % conversion.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140528&req=5

pone-0022526-g002: Phenotypic analysis of leukocytes migration interference by distinct doses of met-RANTES treatment.C57Bl/6 mice were infected orally with AA, treated with met-RANTES at 0.5 and 5 mg doses or (V) veicule and (-) non treated, sacrificed at day 30 post-infection and evaluated for relative number of: A) F4/80+; B) CD3+; C) Gr1+; and D) CD19+ cells in periodontal tissues of WT non-treated versus vehicle, 0.5 mg and 5 mg met-RANTES treated mice by flow cytometry, all performed as described in Material and methods. Results demonstrate the relative number of cells in % when compared with untreated group. Different italic low case letters represent statistically significant differences among the doses in the same experimental group (P<0.05; One-way ANOVA), statistical analysis performed with raw data before % conversion.
Mentions: In order to determine the mechanisms underlying the differential response to 0.5 and 5 mg met-RANTES doses, we initially investigated the interference of the distinct doses in the migration of F4/80+, CD3+, Gr1+ and CD19+ cells (Fig. 2). The 0.5 mg dose resulted in a significant reduction in the relative number of F4/80+ and CD3+ cells, while no differences was observed in the reduction of relative number of Gr1+ and CD19+ cells when compared with non-treated and vehicle-treated mice. Differently, the 5 mg met-RANTES protocol reduced the relative % of F4/80+, CD3+, Gr1+ and CD19+ cells in the periodontal tissues when compared with 0.5 mg of MetRANTES.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, School of Dentistry of Bauru, São Paulo University-FOB/USP, Bauru, Sao Paulo, Brazil.

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.

Show MeSH
Related in: MedlinePlus