Optimal host resistance to microbial pathogens requires the selective activation of a particular cellular of humoral immune response. Delayed-type hypersensitivity responses medicated by Th1 cells are required to combat infection with obligate intracellular organisms, whereas Th2 cells are beneficial in infections with extracellular organisms, including oral pathogens. New immunization strategies developed by us and others show great promise in directing responses toward either a Th1 or Th2 phenotype. Infections of the dental pulp result in pulpal necrosis and the resorption of periapical bone. During the prior grant period, we found that pulpal infection elicits predominantly Th1-type pro-inflammatory responses, and that periapical bone resorption is dramatically inhibited by the endogenously expressed anti-inflammatory Th2 cytokine IL-10. In the proposed studies, we will test the hypothesis that these novel immunization strategies can be used to skew responses against the model organism P.gingivalis toward a Th2 phenotype, resulting in increased IL-10 expression and reduced periapical bone resorption.
In Aim 1, mouse strains that are genetically susceptible or resistant to P. gingivalis-induced periapical bone resorption will be identified. T cell lines from a resistant strain will be used to identify P.gingivalis antigens that preferentially stimulate IL-10 responses, using expression cloning (Aim 2).
Aim 3 will determine if immunization with P. gingivalis antigens can inhibit periapical bone resorption in vivo. The mechanism(s) by which P.gingivalis antigens induce IL-10 responses will be characterized in Aim 4. The goal of these studies is to devise new methods for immunomodulating proinflammatory pathways and bone resorption via preferential induction of IL-10.
|AlShwaimi, Emad; Berggreen, Ellen; Furusho, Hisako et al. (2013) IL-17 receptor A signaling is protective in infection-stimulated periapical bone destruction. J Immunol 191:1785-91|
|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|
|Sasaki, H; Suzuki, N; Alshwaimi, E et al. (2010) 18*-glycyrrhetinic acid inhibits periodontitis via glucocorticoid-independent nuclear factor-*B inactivation in interleukin-10-deficient mice. J Periodontal Res 45:757-63|
|AlShwaimi, Emad; Purcell, Patricia; Kawai, Toshihisa et al. (2009) Regulatory T cells in mouse periapical lesions. J Endod 35:1229-33|
|Sasaki, Hajime; Suzuki, Noriyuki; Kent Jr, Ralph et al. (2008) T cell response mediated by myeloid cell-derived IL-12 is responsible for Porphyromonas gingivalis-induced periodontitis in IL-10-deficient mice. J Immunol 180:6193-8|
|Leshem, Onir; Kashino, Suely S; Goncalves, Reginaldo B et al. (2008) Th1 biased response to a novel Porphyromonas gingivalis protein aggravates bone resorption caused by this oral pathogen. Microbes Infect 10:664-72|
|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|
|Stashenko, Philip; Goncalves, Reginaldo B; Lipkin, Brad et al. (2007) Th1 immune response promotes severe bone resorption caused by Porphyromonas gingivalis. Am J Pathol 170:203-13|
|Goncalves, Reginaldo B; Leshem, Onir; Bernards, Karen et al. (2006) T-cell expression cloning of Porphyromonas gingivalis genes coding for T helper-biased immune responses during infection. Infect Immun 74:3958-66|
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