| Food allergies are a growing health concern affecting approximately 6--8% of the US population. In particular, peanut allergy has an estimated prevalence of greater than 1% of the population and is uncommonly outgrown, making it a life-long disease. Ingestion of allergens can lead to a variety of allergic symptoms ranging from hives or gastrointestinal symptoms to constriction of the airways and anaphylactic shock. Because there is currently no FDA-approved treatment for food allergy, these patients are managed with education and strict allergen avoidance. However, even with the most careful avoidance, accidental ingestion does occur and can lead to life-threatening anaphylaxis. As a result, treatment options are needed. Treatments currently under investigation in clinical trials include peanut oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT), though mechanisms of these therapies remain unclear. While results from these trials are promising, limitations include daily dosing, adverse effects, and limited long-term efficacy after therapy is discontinued. Thus, there remains an urgent need for improved therapy options. The work in this dissertation provides the foundation for future drug discovery. First, IgG-mediated basophil inhibition was elucidated as a mechanism of OIT and SLIT and was shown to be associated with long-lived protection. Understanding this mechanism further may result in a targeted therapy option. Separately, a therapy targeting inhibitory receptors on antigen-specific B cells was developed for the prevention of sensitization in a mouse model of peanut allergy. Unfortunately, understanding of food allergy etiology and advances in treatment options has been limited by the lack of an animal model that accurately recapitulates the human disease. Here, we describe the use of the genetically diverse Collaborative Cross to identify CC027/GeniUnc as a more relevant mouse strain that exhibits a severe reaction following oral sensitization and challenge. Together, this work provides a platform for better understanding the mechanisms of food allergy and its treatments, as well as the development of new therapies. |
