(603e) Local Induction of Endogenous Regulatory T Cells for the Treatment of Periodontal Disease

Authors: 
Greene, A., University of Pittsburgh
Shehabeldin, M., University of Pittsburgh
Ratay, M., University of Pittsburgh
Sfeir, C., University of Pittsburgh
Little, S. R., University of Pittsburgh
Periodontitis (periodontal disease) is one of the most prevalent diseases today, affecting over 65 million adults in the United States alone. The disease is characterized by an overburden of invasive bacteria, gum inflammation and plaque buildup. Over time, these symptoms result in severe loss of gingival tissue attachment, tooth loss and bone resorption. Periodontitis is also correlated to higher incidences of respiratory disease, cardiovascular disease and even diabetes. Although current treatment targets the oral bacterial load through the administration of local antibiotics and procedures such as scaling and root planing, they do not address the root cause of the disease. Specifically, more recent studies suggest that although overburden of invasive bacteria is what initiates the disease, it is an unbalanced inflammatory response that propagates disease symptoms. Interestingly, in the healthy steady state, the body naturally combats destructive inflammation and imbalanced inflammatory responses through regulatory pathways mediated by cells such as regulatory T-cells (Tregs). Consequently, we have sought to target this underlying immune imbalance through increasing the local presence of regulatory lymphocytes (Tregs) in order to restore local, immunological homeostasis. Previously, we demonstrated that the presence of 3 factors ; IL-2 (cytokine- promotes the differentiation of immature T cells into regulatory T cells), Rapamycin (small molecule- mTorr inhibitor to prevent differentiation into to Tcell types) and TGF-β (cytokine- growth factor essential for Treg differentiation) robustly induces the transformation of naïve CD4+ lymphocytes into FoxP3+, suppressive Tregs. Accordingly, we hypothesized that utilizing a local delivery of Treg-inducing factors could effectively treat the immune-mediated destruction observed in periodontal disease by increasing the local number of Tregs. Accordingly, we formulated 3 separate controlled release systems that can be locally placed in the periodontal space as a depot (degradable microspheres composed of polymers that have an excellent track record of FDA approval). Using the periodontopathogen Porphyromonas gingivalis (Pg) to induce periodontal disease in a Balb/c mouse model, we have demonstrated that this combination of factors significantly decreases alveolar bone loss in mice. A shift in microenvironment has also been demonstrated with an analysis of pro-inflammatory and anti-inflammatory markers. Ultimately, the use of these Treg-inducing microparticles significantly improves periodontitis outcomes and may be able to serve as a platform delivery system to treat other inflammatory diseases.