Abstract

The long-term goal of this study is to understand immune tolerance to oral bacteria in the context of periodontal inflammation. In the healthy individuals, immune tolerance seems to be developed to these bacteria, similar to the intestinal situation where tolerance is induced to commensal bacteria as well as dietary antigens. Preliminary results demonstrated that oral infection with Actinobacillus actinomyceremcomitans (Aa) induced immunological tolerance. Passive induction of Th1-immune response to the bacteria resulted in inflammatory bone resorption by RANKL expressing Th1-type cells. In order to elucidate the mechanism of tolerance to oral commensal bacteria, I propose to study the role of such tolerance in preventing inflammatory bone resorption in an experimental animal model. It is well documented that IL-10 is associated with induction of tolerance. The significance of IL-l0 in the induction of tolerance to oral bacteria will be studied in a mouse model of periodontal disease. We will further search the influence of vasoactive intestinal protein (VIP) on the oral immune system in association with tolerance development. VIP is produced by lymphocytes and possess immune suppressive function, demonstrated by induction of IL- 10 and down-regulation of proinflammatory cytokine production by macrophages. Among at least 20 of neuropeptides that are produced by lymphocytes, only VIP and pituitary adenylate cyclase-activating polypeptide (PACAP) which share a family of receptors, exert anti-inflammatory functions. Although VIP has been detected in saliva and produced by gingival epithelial cells, the significance of VIP in the course of tolerance induction in the oral cavity is totally unknown. Therefore, the role of VIP on tolerance to oral bacteria and therapeutic application of VIP will be examined in the mouse model. Our goal is to characterize the tolerance to the oral bacteria in association with lymphocyte mediated periodontal inflammation. This goal will be pursued under the following specific aims.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Career Transition Award (K22)
Project #
3K22DE014551-02S1
Application #
6902112
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Hardwick, Kevin S
Project Start
2002-08-01
Project End
2006-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$864
Indirect Cost

  Institution

Name
Forsyth Institute
Department
Type
DUNS #
062190616
City
Cambridge
State
MA
Country
United States
Zip Code
02142

  Publications

Han, Xiaozhe; LaRosa, Karen B; Kawai, Toshihisa et al. (2014) DNA-based adaptive immunity protect host from infection-associated periodontal bone resorption via recognition of Porphyromonas gingivalis virulence component. Vaccine 32:297-303
Franco, Gilson C N; Kajiya, Mikihito; Nakanishi, Tadashi et al. (2011) Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo. Exp Cell Res 317:1454-64
Rezende, Taia Maria Berto; Vieira, Leda Quercia; Sobrinho, Antonio Paulino Ribeiro et al. (2008) The influence of mineral trioxide aggregate on adaptive immune responses to endodontic pathogens in mice. J Endod 34:1066-71
Han, Xiaozhe; Kawai, Toshihisa; Taubman, Martin A (2007) Interference with immune-cell-mediated bone resorption in periodontal disease. Periodontol 2000 45:76-94
Kawai, T; Paster, B J; Komatsuzawa, H et al. (2007) Cross-reactive adaptive immune response to oral commensal bacteria results in an induction of receptor activator of nuclear factor-kappaB ligand (RANKL)-dependent periodontal bone resorption in a mouse model. Oral Microbiol Immunol 22:208-15
Ernst, C W O; Lee, J E; Nakanishi, T et al. (2007) Diminished forkhead box P3/CD25 double-positive T regulatory cells are associated with the increased nuclear factor-kappaB ligand (RANKL+) T cells in bone resorption lesion of periodontal disease. Clin Exp Immunol 148:271-80
Hosokawa, I; Hosokawa, Y; Komatsuzawa, H et al. (2006) Innate immune peptide LL-37 displays distinct expression pattern from beta-defensins in inflamed gingival tissue. Clin Exp Immunol 146:218-25
Kawai, Toshihisa; Matsuyama, Takashi; Hosokawa, Yoshitaka et al. (2006) B and T lymphocytes are the primary sources of RANKL in the bone resorptive lesion of periodontal disease. Am J Pathol 169:987-98
Valverde, P; Kawai, T; Taubman, M A (2005) Potassium channel-blockers as therapeutic agents to interfere with bone resorption of periodontal disease. J Dent Res 84:488-99
Taubman, Martin A; Valverde, Paloma; Han, Xiaozhe et al. (2005) Immune response: the key to bone resorption in periodontal disease. J Periodontol 76:2033-41

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