Periodontitis is a chronic inflammatory disease that affects 30-40% of the U.S. population. It is the leading cause of periodontal tissue destruction and tooth loss. To date, we cannot accurately predict which individuals will develop future periodontal bone destruction, leading most dental patients to undergo unnecessary treatment and exposure to undue risk. The periodontal microbiota constantly challenges the immune system, leading, in some cases, to chronic inflammation that may end in alveolar bone destruction. Inhibiting such immune responses before bone damage occurs must become the target of prevention. Our long-range goal is to define the cellular immune phenotype that predisposes an individual to destruction of the connective tissue and bone around teeth subsequent to oral infection with periodontal pathogens. Our current objective is to study the kinetics of activation and phenotype of CD4+ effector T cells specific for two Porphyromonas gingivalis gingipains (RgpA and Kgp) in a mouse strain susceptible (BALB/c) or resistant (C57BL/6) to P. gingivalis-mediated periodontal bone destruction. We hypothesize that in mice genetically susceptible to disease, RgpA- and Kgp-specific CD4+ T helper (Th) cells differentiate into bone destructive IFN-? producing Th1 cells, and into a Th17 phenotype after periodontal bone destruction has been initiated. To test this hypothesis we will use a novel antigen-specific tetramer stain to first, determine the kinetics of activation and phenotype of R/Kgp-specific effector and regulatory CD4+ T cells and the relative amount of alveolar bone destruction in P. gingivalis-colonized BALB/c and C57BL/6 mice. Concurrently, we will define the nature and timing of inflammatory cell infiltrate in the marginal gingiva. Second, we will identify the direct effect of R/Kgp- specific effector Th cells on bone levels using a series of adoptive transfer experiments. Collectively, these data will define which phenotype of R/Kgp-specific Th cells will drive the kinetics of bone destruction or protection in each mouse strain. Furthermore, these results will underpin a subsequent R01 application testing the effect of cytokines and RANKL, specifically produced by R/Kgp-specific CD4+ T cells or isotype-switched B cells, on alveolar bone homeostasis and the role of innate immunity within the marginal gingiva in mouse strains that are susceptible or resistant to periodontal bone destruction. Establishing a framework to predict future periodontal bone destruction is crucial to understanding pathogenesis of periodontal disease progression, customizing periodontal treatment, and ultimately developing a mucosal vaccine against periodontitis.

Public Health Relevance

We currently cannot accurately predict which patient will develop gum disease or even which tooth in a patient with ongoing gum disease will develop bone destruction around it in the future. This lack of knowledge prevents the distinct identification of individuals susceptible to or resistant to periodontitis, leading the patients wih gum disease to undergo potentially unnecessary treatment. Working with an experimental mouse model of bone destruction around teeth, we will determine the characteristics of certain immune cells that recognize the damaging products of one of the bacteria associated with gum disease in mice that are susceptible or resistant to bone destruction around their teeth. The result of this research will help us determine the primary characteristic of the immune cells in mice and potentially in humans susceptible to gum disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DE022858-01A1
Application #
8507349
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Burgoon, Penny W
Project Start
2013-05-01
Project End
2015-03-31
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$228,000
Indirect Cost
$78,000
Name
University of Minnesota Twin Cities
Department
Dentistry
Type
Schools of Dentistry
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455