Grant: Project Grant

Asthma is the most common chronic disease in western populations. Severe asthma uses a disproportionate amount of resources due to the high cost of medications and hospitalizations. Severe asthma is often characterized by inflammation generated by production of chemicals known as T-helper 2 type (Th2) cytokines, which include IL-5 and IL-13. These cytokines are released in response to exposure to allergens like house dust mites, pollens, and pets; following environmental pollutants; and as a response to certain infections. B-lymphocytes are key to initiation of Th2 inflammation, as they produce the antibody IgE after exposure to Th2 cytokines. IgE captures inhaled antigens and triggers allergic reactions in the airways. While Th2-stimulated B-cells produce IgE, they also secrete regulatory molecules; in this proposal, we will demonstrate a novel B-cell regulatory pathway: Th2-induced extracellular vesicles (EV) derived from B-cells, which can inhibit eosinophil growth and decrease pulmonary inflammation. EV are small, lipid-membrane based vesicles, which are an important way of transferring information between cells. Using our mouse model of allergic airway inflammation, we will demonstrate the effect of B-cell derived EVs on eosinophil maturation and function. We will also examine the impact of a group of 10 micro-RNA (miRNA), small inhibitory mRNA, which are found in high concentration in B-cell derived EV and can inhibit inflammatory genes induced in allergic airway conditions. If successful, this combination of miRNA can be produced in B-cells, or synthetically produced and packaged in liposomes, and ultimately used to mitigate Th2 inflammation. These novel EVs represent a potential template for development of new multimodal biological therapies.