Oral treatment with complement factor C5a receptor (CD88) antagonists inhibits experimental periodontitis in rats

Breivik, Torbjørn; Gundersen, Yngvar; Gjermo, Per; Taylor, Stephen M.; Woodruff, Trent M.; Opstad, P. K.

doi:10.1111/j.1600-0765.2011.01383.x

Cited by 22 publications

(18 citation statements)

References 50 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This readily explains its protective action, which ranged from 52 to 100% inhibition of bone loss depending on the mode of intervention (preventive or therapeutic) and model employed. In a recent ligature-induced periodontitis study in rats, chemically similar C5aRA was administered in the drinking water, prior to and during the disease, and was clearly less effective (< 20% inhibition of bone loss) (51); this might be due to the different mode of administration, although the different animal species used might be another contributory factor. In the same study, the authors did not examine the effect of C5aRA treatment on periodontal inflammation or other possible mechanisms underlying their observation (51).…”

Section: Discussionmentioning

confidence: 99%

Local Complement-Targeted Intervention in Periodontitis: Proof-of-Concept Using a C5a Receptor (CD88) Antagonist

Abe

Hosur

Hajishengallis

et al. 2012

The Journal of Immunology

109

146

View full text Add to dashboard Cite

When excessively activated or deregulated, complement becomes a major link between infection and inflammatory pathology including periodontitis. This oral inflammatory disease is associated with a dysbiotic microbiota, leads to the destruction of bone and other tooth-supporting structures, and exerts an adverse impact on systemic health. We have previously shown that mice deficient either in complement C5a receptor (C5aR; CD88) or TLR2 are highly and similarly resistant to periodontitis, suggesting that a crosstalk between the two receptors may be involved in the disease process. Here we show that C5aR and TLR2 indeed synergize for maximal inflammatory responses in the periodontal tissue and uncover a novel pharmacological target to abrogate periodontitis. Using two different mouse models of periodontitis, we show that local treatments with a C5aR antagonist inhibited periodontal inflammation through downregulation of TNF, IL-1β, IL-6, and IL-17 and further protected against bone loss, regardless of the presence of TLR2. These findings not only reveal a crucial co-operation between C5aR and TLR2 in periodontal inflammation, but provide proof-of-concept for local targeting of C5aR as a powerful candidate for the treatment of human periodontitis.

show abstract

Section: Discussionmentioning

confidence: 99%

Local Complement-Targeted Intervention in Periodontitis: Proof-of-Concept Using a C5a Receptor (CD88) Antagonist

Abe

Hosur

Hajishengallis

et al. 2012

The Journal of Immunology

109

146

View full text Add to dashboard Cite

show abstract

“…Clinical studies have been conducted with PMX53 for use in psoriasis and rheumatoid arthritis (50, 70); while the compound demonstrated beneficial safety profiles, it did not significantly reduce synovial inflammation in the arthritis study (71). A derivative of the compound with increased metabolic stability and ability to cross the blood-brain barrier (PMX205) has shown promising effects in a mouse model of Alzheimer’s disease (72) and has recently been tested in models of periodontitis and colitis (73, 74). The technology has undergone several acquisitions, and future plans for the clinical development of PMX53 or PMX205 have not been revealed.…”

Section: The Therapeutic Arsenal To Tackle Complement-related Diseasesmentioning

confidence: 99%

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

Ricklin

Lambris

2013

The Journal of Immunology

203

230

View full text Add to dashboard Cite

With the awareness that immune-inflammatory crosstalk is at the heart of many disorders, the desire for novel immunomodulatory strategies in the therapy of such diseases has grown dramatically. As a prime initiator and important modulator of immunological and inflammatory processes, the complement system has emerged as an attractive target for early and upstream intervention in inflammatory diseases and has moved into the spotlight of drug discovery. While prevalent conditions such as age-related macular degeneration have attracted the most attention, the diverse array of complement-mediated pathologies, with distinct underlying mechanisms, demands a multifaceted arsenal of therapeutic strategies. Fortunately, efforts in recent years have not only introduced the first complement inhibitors to the clinic but also filled the pipelines with promising candidates. With a focus on immunomodulatory strategies, this review discusses complement-directed therapeutic concepts and highlights promising candidate molecules.

show abstract

“…In this model, a silk ligature is placed around molar teeth, resulting in massive local accumulation of bacteria and development of inflammation and bone loss in conventional (but not germ-free) mice or rats [45, 92]. Work by an independent group using a similar ligature-induced periodontitis model in rats showed that PMX205 (an analog of PMX53) inhibits bone loss when administered in the drinking water, although the efficacy (<20% protection vs. controls) [93], was reduced relative to the local administration method (50% protection vs. controls) [57]. These differences in efficacy might be attributed to the different modes of inhibitor administration and/or to the use of different animal species.…”

Section: Complement As a Therapeutic Target In Periodontitismentioning

confidence: 99%

Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches

Hajishengallis

Maekawa

Abe

et al. 2015

Advances in Experimental Medicine and Biology

View full text Add to dashboard Cite

The complement system is a network of interacting fluid-phase and cell surface-associated molecules that trigger, amplify, and regulate immune and inflammatory signaling pathways. Dysregulation of this finely balanced network can destabilize host-microbe homeostasis and cause inflammatory tissue damage. Evidence from clinical and animal model-based studies suggests that complement is implicated in the pathogenesis of periodontitis, a polymicrobial community-induced chronic inflammatory disease that destroys the tooth-supporting tissues. This review discusses molecular mechanisms of complement involvement in the dysbiotic transformation of the periodontal microbiome and the resulting destructive inflammation, culminating in loss of periodontal bone support. These mechanistic studies have additionally identified potential therapeutic targets. In this regard, interventional studies in preclinical models have provided proof-of-concept for using complement inhibitors for the treatment of human periodontitis.

show abstract

Oral treatment with complement factor C5a receptor (CD88) antagonists inhibits experimental periodontitis in rats

Cited by 22 publications

References 50 publications

Local Complement-Targeted Intervention in Periodontitis: Proof-of-Concept Using a C5a Receptor (CD88) Antagonist

Local Complement-Targeted Intervention in Periodontitis: Proof-of-Concept Using a C5a Receptor (CD88) Antagonist

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches

Contact Info

Product

Resources

About