The most dramatic food hypersensitivity reaction is systemic anaphylaxis, in which vasoactive mast cell mediators induce plasma extravasation, shock, cardiopulmonary collapse and death (Finkelman, 2007; Simons, 2010). all triggered when food proteins recognized by FcRI-bound IgE induce mast cell activation. The most dramatic food hypersensitivity reaction is systemic anaphylaxis, in which vasoactive mast cell mediators induce plasma extravasation, shock, cardiopulmonary collapse and death (Finkelman, 2007; Simons, 2010). The standard of care, namely recommendation to strictly avoid foods to which they are allergic, paradoxically deprives patients of the chance to naturally develop oral tolerance, as would likely occur if they were able to continue to ingest them without experiencing harmful effects. Following the very successful example of subcutaneous immunotherapy in which subjects with aeroallergen sensitivity are desensitized by injection of protein extracts (allergy shots), investigators have evaluated oral desensitization strategies for food allergy (Nowak-Wegrzyn and Sampson, 2011; Vickery and Pyrithioxin Burks, 2010). Although achieving substantial success, such approaches are associated with unpredictable IgE antibody-mediated allergic reactions limiting their application in practice. Several groups have now performed oral desensitization under cover of the monoclonal anti-IgE antibody, omalizumab, which effectively blocks food anaphylaxis, with the expectation that inhibiting IgE-mediated reactions would improve the patient experience (Nadeau et al., 2011; Schneider et al., 2013). A growing body of evidence indicates that IgE antibodies and mast cells might serve not only as the effectors of immediate hypersensitivity in subjects with Pyrithioxin established sensitivity but also as amplifiers during initial antigen exposure in na?ve subjects, potentially providing early signals for nascent Th2 cell and antibody responses. IgE induces mast cell production of both Th2 cell-inducing and DC-activating cytokines (Asai et al., 2001; Kalesnikoff et al., 2001; Kawakami and Kitaura, 2005). We have reported that IgE and mast cells enhance immune sensitization in contact sensitivity (Bryce LTBR antibody et al., 2004). Using an adjuvant-free asthma model, Galli and colleagues demonstrated that the induction of airway inflammation and bronchial hyper-reactivity are strongly amplified by mast cells in the airway mucosa (Nakae et al., 2007a; Nakae et al., 2007b). Additional evidence that effector cells of allergic responses might independently function as inducers of immune sensitization comes from studies implicating basophils (which, like mast cells, are FcRI+) as early drivers of Th2 cell expansion. (Mukai et al., 2005; Sokol et al., 2009). We similarly hypothesized that IgE antibodies and mast cells might serve not only as the effectors of food anaphylaxis but also as important early inducers of Th2 cell responses and suppressors of Treg cell responses to food allergens and that they might provide an accessible therapeutic handle by which to dampen such responses. Evaluation of this hypothesis required an animal model of food allergy in which immune sensitization could be accomplished directly by enteral sensitization and in the absence of the immunostimulatory effects of prior systemic parenteral immunization or ingestion of immunological adjuvants commonly used in food allergy models. For this purpose we took advantage of inherently atopic mice in which a mutation (F709) of the IL-4 receptor -chain (IL-4r) ITIM results in amplified signaling upon interaction with IL-4 or Pyrithioxin IL-13, but not constitutive activation. These mice exhibit enhanced Th2 cell responses and IgE production, and susceptibility to anaphylaxis following ingestion of the model antigen ovalbumin (OVA) in Pyrithioxin the absence of Pyrithioxin adjuvant (Mathias et al., 2011). We have now adapted this model to the clinically relevant food allergen, peanut, and have applied multiple parallel approaches that together provide strong evidence that IgE antibodies and mast cells enhance Th2 cell responses to ingested allergens. The mechanism for this Th2.