This project is focused on three aspects in the development of novel genetically engineered mucosal immunogens constructed primarily from a saliva-binding region (SBR) of surface protein AgI/II of Streptococcus mutans and a nontoxic component of cholera toxin (CT), the A2/B subunits, as potential candidates for inclusion in a vaccine against dental caries.
Specific Aim 1 will address the mechanisms underlying immunological memory that maintains long-term and recallable salivary IgA antibody responses when SBR-CTA2/B is administered to mice by the intranasal route, which has previously been shown to be particularly effective for inducing these responses. The following will be investigated: the generation and characteristics of antigen-specific memory B and T cells, and the cytokines they produce, in the nasal lymphoid tissue and the cervical lymph nodes that drain it; the ability of these cells to serve as precursors of IgA antibody-secreting cells in salivary glands; and the uptake and retention of antigen by these tissues.
Specific Aim 2 will develop and refine further mucosal immunogens based on the same technology, to improve the production and immunological properties of SBR-CTA2/B, to construct and evaluate immunogens from other segments of AgI/II that may be important for protection against dental caries, and to evaluate the use of similar immunogens constructed from S. mutans glucosyltransferase. The immunogens will be evaluated for their immunogenicity in terms of the salivary IgA and serum antibodies induced in mice when administered by the intragastric and intranasal routes.
Specific Aim 3 will determine the ability of SBR-CTA2/B to induce salivary IgA and serum antibody responses to S. mutans AgI/II in adult human volunteers immunized orally or intranasally with this immunogen. This is planned as a small-scale, preclinical experiment, that takes advantage of the known safety and immunogenicity of CTB itself when administered to humans by these routes, and the previously demonstrated ability of CTB to serve as a carrier for other protein antigens coupled to it either chemically or genetically when these are administered to experimental animals by oral or intranasal routes. The information obtained will permit clinical trials to be proposed for the evaluation of these and similar immunogens are vaccines against dental caries, and demonstrate the utility of this technology for inducing mucosal immune responses that may be applicable against other human infections.
|Zhao, W; Zhao, Z; Russell, M W (2011) Characterization of antigen-presenting cells induced by intragastric immunization with recombinant chimeric immunogens constructed from Streptococcus mutans AgI/II and type I or type II heat-labile enterotoxins. Mol Oral Microbiol 26:200-9|
|Russell, Michael W; Mestecky, Jiri (2010) Tolerance and protection against infection in the genital tract. Immunol Invest 39:500-25|
|Mestecky, Jiri; Russell, Michael W (2009) Specific antibody activity, glycan heterogeneity and polyreactivity contribute to the protective activity of S-IgA at mucosal surfaces. Immunol Lett 124:57-62|
|Liang, Shuang; Hosur, Kavita B; Nawar, Hesham F et al. (2009) In vivo and in vitro adjuvant activities of the B subunit of Type IIb heat-labile enterotoxin (LT-IIb-B5) from Escherichia coli. Vaccine 27:4302-8|
|Ostberg, K L; Russell, M W; Murphy, T F (2009) Mucosal immunization of mice with recombinant OMP P2 induces antibodies that bind to surface epitopes of multiple strains of nontypeable Haemophilus influenzae. Mucosal Immunol 2:63-73|
|Mestecky, Jiri; Russell, Michael W; Elson, Charles O (2007) Perspectives on mucosal vaccines: is mucosal tolerance a barrier? J Immunol 179:5633-8|
|Nawar, Hesham F; Arce, Sergio; Russell, Michael W et al. (2007) Mutants of type II heat-labile enterotoxin LT-IIa with altered ganglioside-binding activities and diminished toxicity are potent mucosal adjuvants. Infect Immun 75:621-33|
|Liang, Shuang; Wang, Min; Triantafilou, Kathy et al. (2007) The A subunit of type IIb enterotoxin (LT-IIb) suppresses the proinflammatory potential of the B subunit and its ability to recruit and interact with TLR2. J Immunol 178:4811-9|
|Arce, Sergio; Nawar, Hesham F; Muehlinghaus, Gwendolin et al. (2007) In vitro induction of immunoglobulin A (IgA)- and IgM-secreting plasma blasts by cholera toxin depends on T-cell help and is mediated by CD154 up-regulation and inhibition of gamma interferon synthesis. Infect Immun 75:1413-23|
|Hajishengallis, George; Tapping, Richard I; Martin, Michael H et al. (2005) Toll-like receptor 2 mediates cellular activation by the B subunits of type II heat-labile enterotoxins. Infect Immun 73:1343-9|
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