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.
|Jiang, Shaoyun; Hu, Yang; Deng, Shu et al. (2018) miR-146a regulates inflammatory cytokine production in Porphyromonas gingivalis lipopolysaccharide-stimulated B cells by targeting IRAK1 but not TRAF6. Biochim Biophys Acta Mol Basis Dis 1864:925-933|
|Yu, X; Hu, Y; Freire, M et al. (2018) Role of toll-like receptor 2 in inflammation and alveolar bone loss in experimental peri-implantitis versus periodontitis. J Periodontal Res 53:98-106|
|Zhao, Qian; Hu, Yang; Deng, Shu et al. (2018) Cytidine-phosphate-guanosine oligodeoxynucleotides in combination with CD40 ligand decrease periodontal inflammation and alveolar bone loss in a TLR9-independent manner. J Appl Oral Sci 26:e20170451|
|Wang, Yuhua; Yu, Xiaoqian; Lin, Jiang et al. (2017) B10 Cells Alleviate Periodontal Bone Loss in Experimental Periodontitis. Infect Immun 85:|
|Liu, Zhiqiang; Hu, Yang; Yu, Pei et al. (2017) Toll-like receptor agonists Porphyromonas gingivalis LPS and CpG differentially regulate IL-10 competency and frequencies of mouse B10 cells. J Appl Oral Sci 25:90-100|
|Yu, Pei; Hu, Yang; Liu, Zhiqiang et al. (2017) Local Induction of B Cell Interleukin-10 Competency Alleviates Inflammation and Bone Loss in Ligature-Induced Experimental Periodontitis in Mice. Infect Immun 85:|
|Zhuang, Zehang; Xie, Nan; Hu, Jing et al. (2017) Interplay between ?Np63 and miR-138-5p regulates growth, metastasis and stemness of oral squamous cell carcinoma. Oncotarget 8:21954-21973|
|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|
|Shi, J; Liu, Z; Kawai, T et al. (2017) Antibiotic administration alleviates the aggravating effect of orthodontic force on ligature-induced experimental periodontitis bone loss in mice. J Periodontal Res 52:725-733|
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