Studies are proposed to determine the major mode of induction of secretory IgA (S-IgA) responses and the mechanisms involved in its regulation in higher primates (monkeys) and humans to antigens of Streptococcus mutans. Studies performed mainly in rodents and rabbits have provided convincing evidence for a common mucosal immune system. However, evidence for a common mucosal immune system in humans has been indirect. It has been shown that ingestion of S. mutans or other vaccines by humans results in the simultaneous appearance of S-IgA antibodies in external secretions, and that specific antibody-forming cells (AFC) occur in the peripheral blood prior to this S-IgA response. In the studies proposed, monkeys will be used to: 1) establish that enteric immunization with S. mutans whole cell vaccine induces S-IgA responses; 2) assess cellular and humoral aspects of the primary and secondary anti-S. mutans responses and evaluate if the immunization regimen resulted in the induction of oral tolerance; and 3) determine if specific S-IgA responses induced to antigens of S. mutans can be augmented by the oral adjuvant muramyl dipeptide and protect against dental caries. In humans orally immunized with S. mutans vaccines, we will: 1) measure in serum and external secretions the level and isotype (including IgA subclasses) of antibodies to selected S. mutans antigens; and 2) establish the origin of AFC B cell precursors present in the peripheral blood by measuring their potential of secrete polymeric IgA1 and IgA2 antibodies. These studies will allow an evaluation of AFC responses to individual antigens of potential importance in protection. In addition, 3) responses to auto-antigens will be evaluated. In other studies, antigen-specific T cells will be purified from the peripheral blood of orally immunized humans and representative clones on both T helper (Th) and T suppressor (Ts) cells will b derived. Thus, we will characterize human regulatory T cells for IgA responses (Th) and for systemic unresponsiveness (Ts) (oral tolerance). Finally, a molecular analysis of T cell factors involved in mucosal immune responses will be accomplished by lameda phage cDNA cloning. These studies will allow a molecular understanding of lymphocyte regulation of mucosal immune response, key elements which account for the common mucosal immune response to enteric vaccines.
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