Our first specific aim will be to examine changes with aging in immune responses and regulatory mechanisms stimulated by gut mucosal antigen exposure. Exposure to food antigens, bacteria, viruses and parasites often takes place via the mucosal route. Our past studies showed that antigens encountered in the gut have a major influence on host systemic immune responses. Thus, diminished or absent systemic immune responses to an antigen after exposure to that antigen in the gut appears to be an important facet of the host's interaction with many different antigens in the gastrointestinal tract. Using methods developed in this laboratory, we will define and characterize changes that may occur with age in host immune reponses resulting from exposure to gut antigens. Abnormalities in mechanisms regulating the host-environment interaction with gut antigens may be important in the development of increased susceptibility to microbial disease, as well as in the development of autoimmune, allergic and neoplastic disease in the elderly. The second specific aim of these studies is to characterize the effects of aging on the induction, regulation and isotype expression of anti-polysaccharide antibody responses. There appear to be significant differences between the induction and regulation of antibody responses to bacterial polysaccharide antigens compared to protein antigens. Our observation that BALB/c mice produce substantial age and T-cell dependent IgA Lambda1 antibody responses to Alpha(1,3)glucan determinants on dextran B1355 is a significant new finding and indicates the need to reevaluate previous concepts of the character and regulation of anti-polysaccharide responses. Using in vivo methods and our new in vitro culture system for examining antibody responses to polysaccharide determinants, we will characterize and attempt to manipulate the development and regulation of isotype specific anti-polysaccharide antibody responses. These studies are particularly relevant to our understanding of mucosal immune responses and to the development of effective immunization programs for the elderly and very young.
