Periodontitis is an inflammatory disease triggered by host immune response to pathogenic microorganisms in the periodontal biofilm, leading to the loosening and subsequent loss of teeth, and increased risk for the development of various systemic conditions. Current treatments do not offer complete amelioration of periodontal tissue destruction because they do not directly address the biological causes of periodontal pathogenesis -- unbalanced, overly aggressive immune responses. There is compelling interest in developing targeted immunological interventions to treat periodontitis before it progresses to an expensive and refractory disease. B cells with a regulatory function (BREG) 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 goal of this project is to characterize in vitro activated and expanded BREG in response to Toll-like receptor (TLR) agonists and co-stimulatory molecules, and to test these BREG to ameliorate periodontal bone resorption in vivo in a mouse model of experimental periodontal disease. We will then characterize the phenotype and immune regulatory function of human BREG in vitro using human peripheral blood mononuclear cells (PBMC) and gingival mononuclear cells (GMC). The central hypothesis of this project is that enhancing local BREG function can reduce immune-mediated periodontal disease bone loss. The three related and overlapping specific aims are: 1) Determine the activation and expansion of BREG from mouse spleen and intraperitoneal cavity and characterize the phenotypic markers that can be used to define such populations. The focus will be the interactions among multiple TLRs (TLR2, 4 and 9) on the activation of BREG and how such BREG be expanded in vitro. 2) Evaluate in vivo trafficking and the effects of adoptively transferred BREG on periodontal bone resorption using a mouse model of periodontal disease. Particular emphasis will be on the effect of transferred BREG on the RANKL production in local inflamed gingival tissues. 3) Characterize in vitro activated and expanded human BREG from PBMC of healthy and diseased individuals and more definitively, evaluate the effectiveness of the proposed regimes on GMC from periodontitis patients. Study of GMC associated with ongoing disease will enable us to determine the effect of the most promising regimens on BREG in a manner similar to treatment during disease, as the first step towards translational applications. Successful completion of this project would be expected to pave the way for translational research to delineate BREG-directed amelioration of periodontitis pathogenesis due to the unbalanced, overly aggressive immune responses. Novel strategies to selectively promote local BREG function may enable therapeutics to effectively treat patients with periodontal diseases that are resistant to current therapy.

Public Health Relevance

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. Current treatments do not offer complete amelioration of bone loss around teeth because they do not directly address the biological causes of periodontal bone loss -- unbalanced, overly aggressive host immune responses. This application will provide us new knowledge about balancing host immune response in periodontal disease by promoting immune regulatory functions and will contribute to development of local therapeutic strategies that are effective in preventing tooth loss in people with periodontal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56DE023807-01A1
Application #
8896097
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Melillo, Amanda A
Project Start
2014-08-05
Project End
2015-07-31
Budget Start
2014-08-05
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$476,220
Indirect Cost
$226,220
Name
Forsyth Institute
Department
Type
DUNS #
062190616
City
Cambridge
State
MA
Country
United States
Zip Code
02142