Project Summary: The prevalence of food allergies, such as to peanut or egg, is increasing worldwide, with the number of individuals affected in the US approaching 32 million, ≈10% of the population. For allergic disease, the current standard of therapy involves administration of antihistamines, corticosteroids, and leukotriene inhibitors that only target allergic symptoms. Therapies such as specific immunotherapy target the Th2 bias that underlies allergy, however this requires long periods of dose escalation with soluble antigen and carries a significant risk of adverse reactions. No therapies are currently available to develop tolerance to the antigens. The long-term goal of this research is to develop a nanoparticle (NP) based platform that can be an off-the-shelf treatment for induction of tolerance to specific food allergens to inhibit undesired immune responses, while not affecting the remaining elements of the immune response. Drs. Stephen Miller and Lonnie Shea (co-PIs) have pioneered an approach that was initially applied to autoimmune disease (Type 1 Diabetes, multiple sclerosis) in which NPs are loaded with antigens, which upon intravenous administration, induce of tolerance to the antigen. The NP technology has been licensed and recently successfully completed a Phase 2a study for celiac disease (a Th1 autoimmune disease). With the goal of moving this technology toward the treatment of allergic diseases, we propose to investigate the NP design for allergic disease. The NP delivers the antigen to APCs, yet also influences their phenotype and activation of T cells. The NP properties, such as antigen loading and composition, can influence T cell activation, and we will identify those properties that can tolerize Th2 responses such as IL-4, IL-5, and IL-13 secretion, B cell activation, and effector cell responses such as mast cells and basophils, which are distinct from the Th1/17 responses in autoimmune disease. Notably, the ability to design the physicochemical properties may facilitate translation of the NPs, as achieving good manufacturing practices and clinical approval while avoiding unanticipated side effects may be more easily attainable without the incorporation of an API. Specific Aim 1 will investigate the NP design and modulation of cellular and molecular responses of APCs for the treatment of peanut and egg allergy models, with Dr. O’Konek (co-I) providing expertise in food allergy. We propose to investigate critical attributes of NPs to distinguish i) the impact of NP properties on immune cell polarization, ii) the efficacy of antigen presentation, iii) the in vivo trafficking of the NPs, and iv) the efficacy of tolerance induction in pre-sensitized food allergy disease models. Specific Aim 2 will determine the cellular and molecular mechanisms by which NP delivery affects T cell phenotypes while tolerizing Th2 allergic diseases. Furthermore, the frequency, receptor expression and response of mast cells and basophils to all...