The Mechanisms for Hyper-Immune Responsiveness in Mice Receiving in Utero Ovalbumin Injection

The prevalence of allergy and asthma is gradually increasing in childhood over the past decades. Asthma, a chronic airway inflammation driven by T helper 2 (Th2)-type immunity and characterized by airway hyperresponsiveness, eosinophilic infiltration, and elevated serum IgE levels. The environmental allergens and genetic susceptibility are important risk factors for the development of allergic diseases. The concept of “actively acquired tolerance” suggests that the prenatal allergen intervention might have chance to develop immunotherapy for asthma. However, we observed a totally un-expected result for having Th2-skewed atopy and hyper-responsiveness to postnatal allergen challenge in prenatal allergen exposed mice with ovalbumin (OVA) injection into fetuses on gestational day 14. We also demonstrated that fetal phagocytes processed OVA and differentiated toward dendritic-like cells. These OVA(+)-fetal phagocytes present antigen-presenting function to stimulate CD4+ cell proliferation and produce Th2-cytokines in vitro and in vivo. In addition, the expression of Notch ligands (Jagged 1 and Jagged2) as well as IL-33 was also enhanced in the lungs of neonates. Thus, we propose that the function of OVA-laden phagocytes modulate Th2-biased immune responses is due to the expression of Notch ligands and they also affect the function of type 2 innate lymphoid cells (ILC2). We will firstly examine the expression of Notch ligands on DC-like phagocytes and isolate these cells to test their function for Th2-biased immunity. Then, we will apply γ-secretase and antibodies specific to each Notch ligand to confirm the role of Notch signaling in this asthmatic animal model. With the adoptive transfer of the isolated OVA-laden phagocyte populations, we will examine their effect on ILC2 function. Moreover, whether IL-33 is involved in the regulation of OVA-laden fetal phagocyte to ILC2 will be examined in IL-33 knockout mice. The results in this project will offer a better understanding of the roles of Notch signaling in both innate and adaptive immunity in asthmatic pathogenesis. It will also provide scientific evidence for fetal allergen avoidance as a strategy for allergy prevention. The novel drug for targeting asthma will be developed based on the new concept.

Project ID:PC10901-0051
External Project ID:MOST107-2320-B182-005-MY3