Blocking of mast cell-mediated passive anaphylaxis to peanut using covalent heterobivalent inhibitor in a humanized mouse model

Abstract

Abstract Anaphylaxis to peanut allergen is a severe hypersensitive allergic reaction characterized by life-threatening symptoms. Anaphylaxis is mediated by IgE-dependent mast cell activation that leads to the release of inflammatory mediators. In a previous report, we described the design of a covalent heterobivalent inhibitor (cHBI) that selectively forms covalent bonds with allergen specific-IgE (sIgE) on mast cells and abates allergic reactions in ex-vivo peanut challenges. Here, we utilized a humanized mouse model to recapitulate key features of anaphylaxis to peanut in humans, and we examined the efficacy of cHBI in blocking the anaphylactic reaction in this model. NSGS (NOD-scid Il2rgnull IL-3/GM-CSF/SCF) mice engrafted with human hematopoietic stem cells were treated with an allergen-specific human IgE monoclonal antibody and then challenged with a peanut allergen. We found that the peanut-challenged humanized mice can develop rapid anaphylaxis and mast cell degranulation following challenge. The anaphylactic reaction was characterized by a substantial decline of core body temperatures and upregulation of human mast cell degranulation markers. Additionally, we found that the severity of the anaphylactic reaction is hIgE dose-dependent. Most importantly, cHBI protected the mice from developing an anaphylactic reaction demonstrating the ability of cHBI to block IgE-mediated allergic reactions in the humanized mice. Overall, our results show that the humanized mouse model is a novel model to study human mast cell IgE-mediated allergic reactions and demonstrate that cHBI is an effective potential therapeutic inhibitor for food allergy.