Human periodontal diseases (e.g., periodontitis) are heterogeneous and result from specific bacteria-host immune interactions. Periodontitis is the major cause of tooth loss in adults and has been recognised as a significant risk factor associated with coronary heart disease, stroke and bacterial pneumonia. The long-term objective of this research program is to identify bacterial antigens important for immune and inflammatory responses in human periodontitis. Engraftment of immunodeficient NOD/SCID mice with human peripheral blood leukocytes (HuPBL) provides an excellent model for studying immune responses to inoculated pathogens. The applicant proposes to use this unique system and a well characterized clinical entity, Actinobacillus actinomycetemcomitans:Aa-associated localized juvenile periodontitis (LJP), to study the immune basis of human periodontitis, for which no animal model exists and which, for ethical and practical reasons, cannot be directly studied in humans. The applicant has shown that oral inoculation of live Aa into NOD/SCID mice carrying high levels of (up to 60 percent) HuPBL from periodontitis patients can be achieved. Further, engrafted human leukocytes present in mouse periodontal tissues can functionally respond to Aa challenge. Therefore, microbial antigen-specific immune responses of LJP can be studied in this model.
The specific aims of this proposal are: 1) to identify Aa-antigens involved in LJP using a genetic screening approach, and 2) to assess the periodontal immune responsiveness elicited by the identified Aa-antigens in the current animal model. Identification of Aa-antigens will be achieved by screening an Aa genomic-DNA library in transformed E. coli. This would allow the expressed Aa-antigens to be captured by patient's antigen-presenting cells which will present and activate the same host's periodontal CD4+T-cells carrying an activation marker for visual identification as probes. The Aa antigens identified will be assess by in vitro T-cell activation (by IL-2) and B-cell IgG antibody (by ELISA) assays for specificity and correlation analyses in LJP and LJP-free subjects. The new information obtained from the proposed studies will provide rationales and hypotheses to investigate the clinical correlates and significance for important bacterial antigens involved in Aa- associated LJP. Further, it will increase our knowledge of host immune-parasite interactions and could eventually lead to the development of new protocols (e.g., Mabs or vaccines) for the treatment of human periodontal diseases. Therefore, the patient's periodontal health will be improved, thereby their complications and health-care costs will be reduced.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Small Research Grants (R03)
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NIDCR Special Grants Review Committee (DSR)
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Mangan, Dennis F
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University of Western Ontario
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N6 3-K7
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