DEVELOPMENT AND COMPETENCE OF NEONATAL MUCOSAL IMMUNITY

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The humoral and cellular mucosal immune systems likely play a critical role in protecting neonates against many bacterial and viral pathogens that infect or invade via the gastrointestinal or respiratory mucosae. However, our knowledge about the ontogeny and maintenance of these systems starting at birth is very limited. From many studies of germ-free vs. conventionally reared laboratory animals we do know that the development and maintenance of many elements of the mucosal immune system depend on continuous local stimulation of the gut mucosa by environmental antigens. Presumably, these stimuli may begin to act at birth. We aim to analyze each element of the mucosal immune system of developing neonatal mice -- the competence to generate IgA preplasmablasts and memory cells vis a vis germinal center reactions in Peyer's patches, the early contributions of B-1 B cells to IgA plasma cells in lamina propria, the development of 'natural' IgA based on the populating of lamina propria with IgA plasma cells, the maturation and activation state of CD4+ T cells in the gut, the establishment of skewed ratios of TH2>>TH1 cells in gut tissues, and the increase in cellularity, functionality, and diversity of subsets of CD8+ T cells in the intraepithelial leukocyte compartment. By using reciprocally crossed scid/scid x +/+ murine parents, raised conventionally or under germ-free conditions, we plan to compare these processes as they occur in neonates in the presence of or 'insulated' and 'isolated' from passive maternal immune effects and/or environmental microbial stimuli. Our second aim is to investigate mechanisms of immunosuppression/immunopotentiation in neonates mediated by maternal antibodies, pathogens, or environmental antigens, and to evaluate methods to overcome or enhance these processes. We particularly aim to establish a role, if any, for bacterial lipopolysaccharide in mediating the maturation of neonatal B cells and in developing the 'natural' gut IgA response. Further, we would like to devise procedures that would allow neonates to benefit from passively acquired maternal antibodies while overcoming their suppression of active, mucosal immunization -- via mucosal adjuvants, microencapsulated antigens, etc. Model gut mucosal stimuli/infectious agents will include Types 1 and 3 reoviruses, Morganella morganii, Escherichia coli, Salmonella typhimurium Lactobacilli sp., Listeria monocytogenes, and segmented filamentous bacteria (an obligate anaerobe).