LAUSR

Peanut-induced allergy is an immunoglobulin E (IgE)–mediated type I hypersensitivity reaction that manifests symptoms ranging from local edema to life-threatening anaphylaxis. Although there are treatments for symptoms in patients with allergies resulting from allergen exposure, there are few preventive therapies other than strict dietary avoidance or oral immunotherapy, neither of which are successful in all patients. We have previously designed a covalent heterobivalent inhibitor (cHBI) that binds in an allergen-specific manner as a preventive for allergic reactions. Building on previous in vitro testing, here, we developed a humanized mouse model to test cHBI efficacy in vivo. Nonobese diabetic–severe combined immunodeficient γc-deficient mice expressing transgenes for human stem cell factor, granulocyte-macrophage colony-stimulating factor, and interleukin-3 developed mature functional human mast cells in multiple tissues and displayed robust anaphylactic reactions when passively sensitized with patient-derived IgE monoclonal antibodies specific for peanut Arachis hypogaea 2 (Ara h 2). The allergic response in humanized mice was IgE dose dependent and was mediated by human mast cells. Using this humanized mouse model, we showed that cHBI prevented allergic reactions for more than 2 weeks when administered before allergen exposure. cHBI also prevented fatal anaphylaxis and attenuated allergic reactions when administered shortly after the onset of symptoms. cHBI impaired mast cell degranulation in vivo in an allergen-specific manner. cHBI rescued the mice from lethal anaphylactic responses during oral Ara h 2 allergen–induced anaphylaxis. Together, these findings suggest that cHBI has the potential to be an effective preventative for peanut-specific allergic responses in patients. Description Blockade of peanut-reactive epitopes prevents systemic anaphylaxis in humanized mice. Inhibiting allergy Specific strategies to prevent anaphylaxis in individuals with food allergy are urgently needed. Here, Alakhras et al. tested a covalent heterobivalent inhibitor (cHBI) specific to peanut Ara h 2 allergen as a treatment for peanut allergy. The cHBI used in this study binds to Ara h 2-specific IgE; this prevents binding of Ara h 2 allergens to IgE and, as a consequence, prevents activation of mast cells. The authors found that treatment of peanut-reactive humanized mice with Ara h 2-specific cHBI protected mice against peanut-induced allergic reactions for more than two weeks. cHBI treatment also conferred protection when given shortly after onset of anaphylactic symptoms, highlighting potential clinical use of cHBI as both a preventative and treatment for food allergy.—CM