Current treatments for periodontitis do not directly address the biological causes of periodontal pathogenesis -- unbalanced, overly aggressive immune responses. Without new strategies to augment current regimens, a substantial number of patients with periodontitis, especially with cases not responsive to current therapies, will continue to suffer the dental and systemic consequences. The long-term goal of our research is to determine immunological strategies that ameliorate periodontal disease in order to promote oral and systemic health. IL- 10-producing regulatory B cells (B10) play a key role in immune system balance, restraining the excessive inflammatory responses by inhibiting pro-inflammatory cytokines and promoting regulatory T cell differentiation. The objective of this application is to determine the mechanism of B10 activation in vitro and B10-mediated abrogation of experimental periodontal bone resorption in vivo. The central hypothesis of this project is that B10 ameliorates periodontal disease bone resorption through antigen-directed gingival migration, and local secretion of IL-10 promotes Treg formation, inhibits Th1 and Th17 activation, and reduces RANKL production. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicants' laboratories supported by a high priority, short-term project award (R56-DE023807). The rationale for the proposed research is that knowledge on how to regulate B10 activity enables novel therapeutic strategies to effectively inhibit the excessive inflammation and bone loss as a local treatment for periodontal disease. The three related specific aims are: 1) To identify the molecular mechanisms for activation and expansion of mouse B10 in vitro. 2) To determine mechanism of B10-mediated abrogation of periodontal inflammation and bone resorption in mouse in vivo. 3) To determine control mechanism of local B10 activation in human gingival mononuclear cells in vitro as first step towards translational research. In vitro B cell isolation/culture system (Aim 1), B cell transfer/ n vivo mouse model of periodontal disease combined with the live cell bioluminescent in vivo imaging approach and quantitative 3-dimentional measurement of periodontal bone loss (Aim 2), and a culture system for in vitro studies using human peripheral blood and gingival tissues obtained from Forsyth Center for Clinical and Translational Research (Aim 3), have all been established as feasible in the applicants' hands. The proposed research is significant because it will enable future development of a novel immunological strategies based on local control of B10 function at the site of periodontal infection and inflammation to treat periodontal disease. The expected outcomes from these aims will be a clear understanding of the mechanisms of B10-meidated abrogation of periodontal bone resorption in vivo in an animal model, and control of B10 function in vitro in local human immune cells from periodontal disease sites.
According to recent findings from the Centers for Disease Control and Prevention (CDC), one out of every two American adults aged 30 and over (64.7 million) has mild, moderate or severe periodontitis, the more advanced form of periodontal disease. If untreated, it can cause jaw bone destruction and ultimately leading to tooth loss. The expenditures for treating these conditions far exceed $10 billion/year in the US. This application is relevant to public health because it will provide us new knowledge about balancing host immune and inflammatory responses in periodontal disease by promoting functions of immune regulatory cells. The proposed research is relevant to the part of NIH's mission that it will contribute to the future development of local therapeutic strategies that are effective in preventing tooth loss in people with periodontal disease.
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|Kanzaki, Hiroyuki; Movila, Alexandru; Kayal, Rayyan et al. (2017) Phosphoglycerol dihydroceramide, a distinctive ceramide produced by Porphyromonas gingivalis, promotes RANKL-induced osteoclastogenesis by acting on non-muscle myosin II-A (Myh9), an osteoclast cell fusion regulatory factor. Biochim Biophys Acta Mol Cell Biol Lipids 1862:452-462|
|Hu, Yang; Yu, Pei; Yu, Xinbo et al. (2017) IL-21/anti-Tim1/CD40 ligand promotes B10 activity in vitro and alleviates bone loss in experimental periodontitis in vivo. Biochim Biophys Acta Mol Basis Dis 1863:2149-2157|
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