Bruton’s tyrosine kinase inhibition effectively protects against human IgE-mediated anaphylaxis

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Abstract

No known therapies can prevent anaphylaxis. Bruton’s tyrosine kinase (BTK) is an enzyme thought to be essential for high-affinity IgE receptor (FcεRI) signaling in human cells. We tested the hypothesis that FDA-approved BTK inhibitors (BTKi’s) would prevent IgE-mediated responses including anaphylaxis. We showed that irreversible BTKi’s broadly prevented IgE-mediated degranulation and cytokine production in primary human mast cells and blocked allergen-induced contraction of isolated human bronchi. To address their efficacy in vivo, we created and utilized what we believe to be a novel humanized mouse model of anaphylaxis that does not require marrow ablation or human tissue implantation. After a single intravenous injection of human CD34+ cells, NSG-SGM3 mice supported the population of mature human tissue-resident mast cells and basophils. These mice showed excellent responses during passive systemic anaphylaxis using human IgE to selectively evoke human mast cell and basophil activation, and response severity was controllable by altering the amount of allergen used for challenge. Remarkably, pretreatment with just two oral doses of the BTKi acalabrutinib completely prevented moderate IgE-mediated anaphylaxis in these mice and also significantly protected against death during severe anaphylaxis. Our data suggest that BTKi’s may be able to prevent anaphylaxis in humans by inhibiting FcεRI-mediated signaling.

Authors

Melanie C. Dispenza, Rebecca A. Krier-Burris, Krishan D. Chhiba, Bradley J. Undem, Piper A. Robida, Bruce S. Bochner