Defining Protective IgGs to Food Allergy

Approximately 2% of the population of Western country is affected by peanut allergies. Peanut oralimmunotherapy OIT has gained traction in the clinic as therapeutic option. However successful peanut OITresulting in tolerance to peanuts or sustained unresponsiveness occurs in only 50% of treated individuals. It isnot known why peanut oral immunotherapy (OIT) induces tolerance to peanut some peanut-allergic individualsbut not others. There are likely multiple contributing factors including differences in OIT-induced peanut-specificIgG specificity and affinity differences in peanut-specific IgG titers differences in peanut-specific IgE titers aswell as the variable induction of peanut-specific T regulatory cells. However a systemic characterization of thepeanut-specific IgG response to OIT has not been conducted. We profiled peanut-specific IgG from peanut-allergic adults who underwent peanut OIT in PNOIT2 trial. Intriguingly a signature of peanut-specific IgG wasidentified in patients that developed sustained unresponsiveness or tolerance to peanuts. Our long-term goalis to understand how glycosylation regulates antibody effector functions enabling therapeutic approaches thatmodulate antibody glycosylation to tailor effector function accordingly. Our central hypothesis is that allergen-specific IgG generated during successful OIT preferentially bind activating FcRs. The rationale for these studiesis that empirically determining the requirements for IgG that are protective against food allergy will enable thedevelopment of novel biologics for food allergies while extensive characterization of the peanut OIT IgGresponse will enable identification of biomarkers that predict the outcome of OIT. We will test our centralhypothesis by pursuing the following specific aims: 1) Define the IgG signatures from peanut OIT that areassociated with OIT outcomes; 2) Determine the requirements for protective IgG during food allergy. Using anapproach that combines biophysics biochemistry cellular and molecular immunology and glycobiology we willdefine the allergen-specific IgG response to OIT from two additional clinical trials and test the IgGs that areidentified in functional models of food-mediated anaphylaxis. In addition to enabling discovery of biomarkerssuccessful peanut OIT these studies will potential outline the requires for IgG that protect from food allergy.