Camille N. Banson
Banson, Camille N.
Faculty / Advisor: Hajishengallis, George
University of Pennsylvania School of Dental Medicine, Department of Basic and Translational Sciences
Periodontitis is an irreversible chronic inflammatory disease of the periodontium that leads to the destruction of the structures supporting the teeth. The high incidence rate of periodontal disease along with multiple systemic diseases associated with it justifies the need to seek improved therapies. Although a pathological microbial community is a necessary component of the disease process, the host inflammatory response to the dysbiotic challenge is the mechanism that directly causes tissue damage, thereby justifying host modulation as a potential therapy. This review summarizes the involvement of complement, an important component of innate immunity, in periodontitis and the therapeutic potential of Cp40/AMY-101, a drug that targets the central complement activation component, C3.Methods
Complement works in synergy with other mediators of the innate immune system, such as toll-like receptors (TLRs). Co-activation of complement and distinct TLRs (TLR4, TLR2/TLR6 and TLR9) resulted in significantly higher levels of tumor necrosis factor (TNF), IL-1β and IL-6 than when each system was activated alone. Complement inhibition also attenuated TLR-mediated proinflammatory responses. Mice deficient in C3 or in complement receptors that are activated downstream of C3, C3a receptor and C5a receptor, were all protected from experimental periodontitis. A third-generation analog of the compstatin family, Cp40, which blocks C3 activation blocked periodontitis in non-human primates and was developed under the name AMY-101 as a potential therapy for human periodontitis.Conclusion
Complement has proven to be a chief mediator of the host immune response. Its involvement in crosstalk with TLR pathways, inflammation, microbial defense and osteoclast activation leads to a robust host immune response but also inflammatory diseases, such as periodontitis, when dysregulated or overstimulated. The ability of Cp40/AMY-101 to inhibit C3 activation and periodontitis (decreased inflammation, bone loss, and clinical attachment loss) in non-human primates has paved the way to the use of this drug for the treatment of the human disease. AMY-101’s performance in locally administered non-human primates rendered it a promising candidate for human clinical trials, which are now underway. This drug can be administered not only therapeutically but also in a preventive setting to populations that are at high-risk of developing periodontitis, such as diabetics and cigarette smokers. In addition to the oral health benefits, it may reduce patients’ risk for developing systemic disease that are linked to periodontitis, such as atherosclerosis, diabetes, and rheumatoid arthritis.