DEVELOPMENT AND COMPETENCE OF NEONATAL MUCOSAL IMMUNITY

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We propose to continue our program concerned with the development and acquisition of competence of the gut mucosal immune system beginning in neonatal life. Our hypothesis is that gut commensal bacteria and enteric viruses drive the normal development of the gut mucosal immune system- humoral and cellular, specific and 'natural'-during neonatal life and act to maintain its 'physiologically normal' state of activation/inflammation. Despite our present appreciation of the roles and protective efficacy of some highly specific mucosal IgA antibodies and mucosal T cells, we know far less about the possible roles of the voluminous amounts of natural' IgA and the abundant 'naturally activated' T lymphocytes in the various compartments of gut-associated lymphoid tissues. Because germ-free adult mice and conventionally-reared neonatal mice share the characteristic of having a markedly underdeveloped gut mucosal immune system, we intend to compare these under controlled conditions of selective colonization with known gut bacteria of enteric viruses (gnotobiotic conditions). Thus we will rely heavily on the use of our now rather rare facility for breeding and maintaining germ-free and gnotobiotic mice. Adult germ-free mice, deliberately colonized with know microbes, provide a more tractable model for subsequent analyses of the development of the gut mucosal immune system in neonatal mice as they develop normally under either conventional or gnotobiotic conditions. We plan to use selected commensal microbes-Morganella, Ochrobactrum, Arthromitis, Helicobater, and Listeria species or mutants,, both facultative and obligate anerobes and both obligate extracellular and facultative intracellular bacteria-to colonize and perturb the 'specific' and 'natural' elements of the mucosal immune system. We plan to analyze, at a cellular and molecular level, how these organisms may drive the development of the mucosal immune system. The practical extension of these studies, which we will pursue, include: 1) mechanisms for 'colonization resistance'; 2) the cellular rationale for long-term secretory IgA mucosal immunity; 3) the bacteria/host gut epithelial interactions that may activate mucosal immunity; 4) the various mechanisms that may result in dissemination of gut bacteria to distant tissues and result in disease or to systemic immune response; 5) the role of gut bacteria in initiating or exacerbating inflammatory bowel disease; and 6) the potential enteric virus/gut bacterial interaction, via the host's gut mucosal immune system, that may affect the outcome of either the viral or the bacterial infection.