The incidence of allergic asthma is increasing at rates inconsistent a purely genetic etiology, suggesting a role for environmental exposures. Early life represents a critical window in which exposure can influence asthma development, and recent evidence suggests that this window extends into the prenatal period. Improvements in air-conditioning technology have allowed us to maintain our homes at temperatures ideal for dust mite growth leading some to speculate that increased mite load may drive increased asthma in the population. Indeed, while prenatal exposure to dietary or pet-derived allergens drive limit allergic sensitization in humans, prenatal house dust mite (HDM) exposure increases sensitization. However, our limited knowledge of the mechanisms whereby maternal exposures influence offspring asthma development, including whether they operate in the pre- or post-natal periods, represent a key knowledge gap. Our preliminary data demonstrate that HDM exposure in pregnancy drives more severe HDM-induced airway hyperresponsiveness (AHR), Th2/Th17 cytokine production, and synthesis of HDM-specific immunoglobulins (Igs) in offspring of exposed mothers. In contrast to other published models demonstrating that maternal OVA (alum) exposures increases offspring sensitivity to both OVA and unrelated allergens, maternal HDM exposure does not increase sensitivity to unrelated respiratory allergens (Aspergillus fumigatus). The unique antigen-specificity of our observations directly inform the overarching hypothesis of the current application: that transfer of allergens and/or allergen specific components (Igs or maternal microchimeric cells (MMcs) are responsible for increased AHR in HDM- challenged offspring of HDM-exposed dams. In this application we will address key questions related to this hypothesis in two aims: 1) to determine if HDM exposure during pregnancy influences asthma development in offspring through prenatal or postnatal mechanisms, we will compare AHR, airway inflammation, HDM-driven Th2 and Th17 cytokine production and HDM-specific Ig synthesis in vaginally or cesarean section delivered offspring of HDM-exposed dams, and in offspring of control dams fostered onto PBS- or HDM-exposed dams. 2) To determine if more severe AHR develops in offspring of HDM-exposed dams through transfer of allergen or components of the maternal adaptive immune system, we will determine if in utero or breast-milk delivered HDM can increase the severity of offspring asthma, determine if preventing adsorption of maternal Igs can reverse the observed effects of maternal HDM exposure, and assess the impact of depletion of MMcs on asthma development in offspring of HDM-exposed dams. The results of this study will enhance our understanding of factors that influence the development of the immune responses that cause allergic asthma, answer major unresolved questions about mechanisms through which maternal exposures can influence offspring asthma, and suggest novel interventions to mitigate the unique effects of maternal HDM exposure on the development of HDM-induced allergic diseases.

Project Narrative While prenatal exposure to dietary or pet-derived allergens induces tolerance, exposure to house dust mite (HDM) in pregnancy is associated with increased sensitization in offspring suggesting that HDM exposure exerts a uniquely pro-asthmatic influence. In this proposal we show that exposure of pregnant mice to HDM enhances severity of HDM-induced asthma, but not severity of asthma in response to other aeroallergens in the offspring of exposed mothers. To better design interventions that mitigate the risk induced by maternal HDM exposure during pregnancy, we will directly test the importance of transfer of HDM, or HDM-specific immune mediators (immunoglobulins, cells) from mother to child either before, or after birth in driving the development of more severe asthma in offspring of HDM-exposed dams.