Anaphylaxis is a systemic allergic reaction to various substances including medications, foods, and stinging insect venom, characterized by acute onset of symptoms such as hives, angioedema, bronchospasm, nausea/vomiting, diarrhea, and/or hypotension. Currently there are no effective treatments capable of preventing anaphylaxis, and the mainstay of treatment is prevention by avoidance of triggers. However, strict avoidance is not always possible, especially in the case of food allergy, so standard of care consists of early recognition of signs and symptoms and the use of injected intramuscular epinephrine after a reaction has occurred [1]. In contrast, there are situations in which a patient is intentionally exposed to an allergen such as during skin testing, allergen immunotherapy (IT), and drug desensitizations, all procedures that carry a risk of a serious systemic reaction. Desensitizations to medications are expensive and labor-intensive, as these typically require inpatient admission due to the risk of potentially lifethreatening reaction [2]. Subcutaneous IT to pollens and venom carries a small but real risk of anaphylaxis with each injection, especially in the build-up phase, so they must be administered under the direct care of a medical professional [3]. While currently there are no approved therapies for food allergy, several recently published clinical trials have demonstrated success in delivering oral and sublingual food proteins to induce a state of desensitization or sometimes even longterm tolerance [1, 4-6]. Some trials have used rapid (LrushL) desensitization protocols, which require inpatient hospitalization with rapid dose escalation over hours to days. As with the risks associated with IT to other substances, food IT also shows potential for significant and/or life-threatening adverse reactions, despite the fact that patients with a history of prior lifethreatening reactions are excluded from enrollment in these trials. Recently, omalizumab (a humanized anti-IgE monoclonal antibody) has been shown in several studies to improve tolerability of rush food IT, but it needs to be started at least 8 weeks (or longer) prior to starting IT, proving it to be costly and not conducive to more urgent situations such as drug desensitizations [7]. Thus, there is an unmet need for therapies that can reduce the rate and/or severity of anaphylactic reactions in the context of accidental exposures as well as during desensitizations and IT.

Allergic anaphylaxis to foods, medications, and venom is mediated by allergens binding to IgE attached to high-affinity IgE receptors (FcεRI) on the surface of mast cells and basophils, thereby cross-linking these receptors, which in turn causes the rapid release of inflammatory mediators such as histamine, prostaglandins, leukotrienes, tryptase, and cytokines. BrutonLs tyrosine kinase (BTK) is an enzyme that is located downstream of FcεRI and is essential for FcεRI-mediated activation of mast cells and basophils [8-11]. The importance of BTK in mediating systemic allergic responses is demonstrated by earlier studies showing that BTK deficient mice have impaired anaphylaxis in a model of passive cutaneous anaphylaxis (PCA)[12]. BTK is also located downstream of the B cell receptor and is important in B cell maturation, signaling, and function. Consequently, congenital BTK deficiency in humans results in X-linked agammaglobulinemia, a disorder characterized by low or absent numbers of circulating B cells and impaired humoral responses to infections. Due to the importance of BTK in B cell activation, pharmacologic inhibitors of BTK have been developed for the treatment of B cell lymphomas and leukemias. Currently there are only two BTK …