Project Summary Allergies are becoming a major cause of neonatal morbidity, with food allergies showing increased incidences and significantly affecting young infants, some of which can be serious or fatal, and are associated with long- term morbidity, imposing heavy social and economic burdens. For neonatal food allergy, no effective treatment is currently available except avoiding or replacing the offending food, which is often impossible due to the ubiquitous nature of some food components. Hence, there is a critical need to identify effective means of strengthening the immune function of neonates to improve their immediate and long-term health. Human respiratory mucosa and blood harbor secreted immunoglobulin D (IgD). We found that IgD is important in respiratory immune defense by inhibiting mucosal adhesion of pathogens and activating antimicrobial and immune-amplifying functions of basophils. IgD activation of basophils also suppresses IgE-induced allergic functions, and increased food allergen-specific IgD production correlates with protection against food allergy after oral immunotherapy in children. Maternal tetanus, diphtheria, and acellular pertussis (TDaP) vaccine and food exposure in pregnancy induces the production of vaccine- and food-specific IgD that is transferred across the placenta to the fetus in humans and mice. The objectives here are to understand the mechanisms of the placental transfer of IgD and to determine if maternal IgD promotes neonatal immune protection against food allergy. We hypothesize that maternal IgD specific to vaccines or food acts as a specific and prophylactic fetal immune education cue to protect neonates against food allergy. Of note, the basophil-activating and anti- allergic functions are unique to IgD and not possessed by IgG. Employing biochemical and imaging techniques in cell culture, human placenta specimens and mouse models, studies in Aim 1 will mechanistically elucidate the placental transfer of maternal IgD. Aim 2 will determine the function of maternal food-specific IgD in the protection against IgE-mediated neonatal food allergy by integrating neonatal mouse models of IgE-mediated food-induced anaphylaxis with human cord or peripheral blood specimens of newborn babies with or without food allergy in the first year of life. Our study is expected to reveal the unique functions of maternal IgD, an ancient yet still mysterious antibody, in neonatal immune function that maternal IgG does not have, but also have a profound impact on improving neonatal health by directing the design of IgD-targeting maternal vaccines or adoptive immunotherapies.