PROJECT SUMMARY Rates of potentially life-threatening IgE mediated food allergy continue to rise, and therapeutic options are limited. Understanding how to alter immune tolerance in patients with food allergy is paramount to the development of new therapies. Two types of food allergen immunotherapy, oral immunotherapy (OIT) and sublingual immunotherapy (SLIT), rely on the administration of gradually increasing amounts of allergen to induce tolerance. For some children, these therapies can induce a state described as remission, where the protection against allergic reactions lasts weeks to months after stopping therapy. While current research has focused on the adaptive immune responses to immunotherapy, the immunologic milieu necessary for these responses is not known. Using metabolomic profiling, the large-scale quantification of metabolites by mass- spectrometry, we identified 3 major pathways (bile acids, arachidonic acids, and histidine metabolites) with known roles in modulating T cell biology that differentiate children who develop remission versus those who do not. The overall goal of this proposal is to determine the role that immunomodulatory metabolites play in the remission of food allergies induced by immunotherapy. In Aim 1, we will validate the presence of protective metabolomic signatures of bile acids, arachidonic acids, and histidine pathways in remission using samples from an interventional trial of OIT in young children. We will then assess how these metabolites change with immune biomarkers of remission (serology, basophil reactivity, and T cell cytokines). While there are many similarities in the mechanisms of OIT and SLIT, there is growing evidence for differences in the pathophysiology of remission induced by these two types of immunotherapy. Based on this, we will study the immunometabolism of remission in SLIT in Aim 2. Using samples from an interventional trial of SLIT, we will characterize the presence of these three immunomodulatory metabolite pathways in remission and assess how these pathways relate to immune biomarkers of remission. Finally, we will compare the metabolomic profiles of SLIT and OIT to identify shared and disparate pathways between the two types of therapy. We anticipate that this work will identify mechanisms of allergic tolerance in immunotherapy and inform the development of new therapies.