Targeting the Development of Type 2 Innate Lymphoid Cells by Adeno-Associated Viral Vector Gene Transfer in Asthmatic Murine Models

Asthma is a complex pulmonary inflammatory disease and it affects about 20% of school children in Taiwan, with the exposure to environmental risk factors and city life style. Generally, it is believed that the susceptible individuals have an abnormal Th2-type immune response to inhaled allergens. According to some previous studies, molecules in innate immunity play pivotal roles in the pathogenesis of asthma. Based on genome-wide studies, these candidate genes include Toll-like receptors (TLRs), -defensin, danger signals, and alarmins. Recently, type 2 innate lymphoid (ILC2) cells have been shown to play important role in the initiation of Th2 activation and following inflammatory responses in the lungs in some allergic animal models. IL-33, the main activator for ILC2 and also one of the alarmins, is involved in asthma pathogenesis. We have an in utero-allergen-induced asthmatic mouse model in which the fetus received OVA on gestational day 14 and re-challenged with allergen after birth. Instead of tolerating the allergen, the mice developed severe asthmatic symptoms upon OVA challenges. Since the precursors of ILCs were found on gestational day 13.5, this model becomes readily tool for us to examine the development of ILC2 numbers and activity in pre-natal exposed asthmatic mice. In this current proposal, we will firstly introduce exogenous secretory IL-33 or IL-3395-270 (has higher affinity to its receptor-ST2) with adeno-associated viral (AAV) vectors that can specifically target lung epithelial cells. Then, the cDNA of soluble ST2 or siRNA to IL-33 will also be administrated into mice of both the adult and in utero OVA-injected asthmatic models. The role of IL-33 in the development of ILC2 cells in these asthmatic models will be examined. Since the interaction between Notch receptors and ligands will also affect the expression of IL-33 in epithelial cells and the transcription factors in ILC2 cells, we will also apply AAV vectors carrying sequences that will modulate the Notch signaling pathways in these asthmatic models. The development of ILC2 cells, Th2-related responses, and lung inflammation will be determined. The results in this project will offer a better understanding of the roles of cells and molecules in innate immunity in asthmatic pathogenesis. The novel therapeutic approaches with those molecules will be developed based on the information obtained from this study.

Project ID:PC10701-0288
External Project ID:MOST105-2320-B182-019-MY3