Secretory immunoglobulin A (S-IgA) is the first major line of defense against numerous pathogens which predominantly infect or invade through mucosal surfaces, including those of the oral cavity. Antigenic stimulation of mucosal inductive sites results in the synthesis and transport of IgA antibodies at effector sites, such as salivary glands, but the mechanisms, including the origin of cells responsible for the production of human salivary S-IgA in particular, are poorly understood. The overall goal of this project is to test the hypothesis that the human mucosal immune system is partly compartmentalized, and that human salivary IgA responses are preferentially generated from proximal inductive sites. Specifically the proposed studies will: 1. Determine the contribution of Waldeyer's ring (tonsils) in the regulation and production of human salivary IgA in different human salivary glands. Levels of IgA (both IgA1 and IgA2) antibodies specific for naturally occurring or routine vaccine antigens in saliva of children with and without tonsils will be measured by ELISA and compared with the levels of antibodies found in serum, and with the numbers of antibody-secreting cells (ASC) in the tonsils. Analysis of the IgA subclass ratios in saliva and serum should indicate the influence of tonsils on these responses. 2. Determine the effects of antigen form, delivery system (liposome- or microsphere-encapsulated antigen), and route of immunization on the IgA subclass distribution and on the quantity of specific S-IgA antibodies in human saliva. Levels of S-IgA antibodies in secretions and of ASC in peripheral blood will be measured in subjects immunized with prototype antigens via different mucosal or systemic routes to determine the proportion of IgA subclasses in the specific salivary antibody response. These studies should determine which route and delivery system is most effective in generating salivary IgA antibody responses. 3. Evaluate memory and duration in the common mucosal immune system with respect to the salivary glands. S-IgA antibody levels in secretions and numbers of circulating ASC will be measured in subjects after a second immunization with a prototype antigen via the same or different mucosal route to determine if more mucosal IgA memory cells induced by prior antigen exposure are recruited for recall responses in salivary glands after intranasal (i.e., proximal) than by peroral (i.e., central) stimulation. Finally, we will 4. Apply the information gained in Specific Aims 2. and 3. to induction of salivary antibodies to Streptococcus mutans antigens relevant for protection against dental caries. S. mutans antigens will be administered mucosally with or without cholera toxin B subunit as a mucosal adjuvant. The quality and quantity of antibody in saliva, nasal wash and serum, and of circulating ASC will be measured after the first and second peroral or intranasal administration of antigen. The results will be relevant to the development of practical immune intervention against oral infections, including dental caries and periodontal disease. Further, the concept of compartmentalization within the human mucosal immune system can be exploited to generate specific mucosal immunity not only in the oral cavity, but also at other sites where protection against pathogens is desire.
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