title: Remote glucosyltransferase-microparticle vaccine delivery induces protective immunity in the oral cavity.
abstract: Intranasally administered dental caries vaccines show significant promise for human application. Alternate mucosal routes may be required, however, to induce caries-protective salivary IgA antibody in children with respiratory diseases. Since rectal mucosa contains inductive lymphoid tissue, we hypothesized that the rectal route could be used to induce salivary immunity to mutans streptococcal glucosyltransferase (GTF), resulting in protective immunity to experimental dental caries. We first explored the ability of glucosyltransferase, incorporated into polylactide-co-glycolide (PLGA) microparticles (MP), and administered rectally together with mucosal adjuvant, to induce a salivary IgA antibody response. Groups of Sprague-Dawley rats (6/group) were immunized rectally on days 0, 7, 14 and 21 with a) GTF-MP alone, b) GTF-MP with cholera toxin, c) GTF-MP with detoxified mutant Escherichia coli toxin (dLT), or d) sham immunized with PLGA and cholera toxin. An additional group was immunized intranasally with GTF-MP alone. Saliva and nasal washes of all intranasally immunized rats contained IgA antibody to glucosyltransferase on day 28. Salivary IgA antibody was also detected in 7/12 rats rectally immunized with GTF-MP and cholera toxin or dLT, although responses were lower than those obtained by intranasal immunization. Most fecal extracts from rectally delivered GTF-MP plus cholera toxin or dLT rats contained IgA antibody to GTF-MP. Low levels of fecal IgA antibody were detected in 3/6 intranasally immunized rats and 2/6 rats rectally immunized with GTF-MP alone. We then examined the extent to which salivary IgA antibody induced by the rectal route could be protective. At 25, 31 and 38 days of age, two groups of female Sprague-Dawley rats (13/group) were rectally immunized with GTF-MP and cholera toxin or with empty microparticles and cholera toxin (sham group). A third group was intranasally immunized with GTF-MP alone. After demonstrating salivary IgA responses to GTF in most GTF-immunized rats, all animals were infected with streptomycin-resistant Streptococcus sobrinus and placed on diet 2000. After 79 days of infection, total caries on molar surfaces were lower in both rectally (7.9 +/- 1.0) and intranasally (7.1 +/- 0.9; P < 0.0.03) immunized groups compared with the sham-immunized group (11.9 +/- 1.6). Smooth surface caries were significantly lower (P < 0.05) in both rectally and intranasally immunized groups. These results support the interconnectedness of the mucosal immune system and indicate that rectal immunization with GTF-MP, together with adjuvant, or intranasal immunization with GTF-MP alone, can induce protective levels of salivary antibody in rats.
authors.affiliation: Department of Immunology, The Forsyth Institute, Boston, MA 02115, USA. dsmith@forsyth.org
authors.forename: D J
authors.initials: DJ
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Lam
authors.forename: L A
authors.initials: LA
authors.lastname: Barnes
authors.forename: W F
authors.initials: WF
authors.lastname: King
authors.forename: Z
authors.initials: Z
authors.lastname: Peacock
authors.forename: D L
authors.initials: DL
authors.lastname: Wise
authors.forename: D J
authors.initials: DJ
authors.lastname: Trantolo
authors.forename: M A
authors.initials: MA
authors.lastname: Taubman
mesh_terms: D000285:Administration, Rectal; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D003731:Dental Caries / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D005964:Glucosyltransferases / Q000276:immunology*; D018928:Immunity, Mucosal; D007071:Immunoglobulin A, Secretory / Q000096:biosynthesis; D019344:Lactic Acid; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley; D012463:Saliva / Q000276:immunology*; D022541:Streptococcal Vaccines / Q000008:administration & dosage*; D013295:Streptococcus mutans / Q000276:immunology; D016986:Streptococcus sobrinus / Q000201:enzymology
chemical_list: D000907:Antibodies, Bacterial; D007071:Immunoglobulin A, Secretory; D011108:Polymers; D022541:Streptococcal Vaccines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005964:Glucosyltransferases