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 (BTKis) would prevent
IgE-mediated responses including
anaphylaxis. We showed that irreversible BTKis 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 used 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 alteration of the amount of
allergen used for challenge. Remarkably, pretreatment with just 2 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 BTKis may be able to prevent
anaphylaxis in humans by inhibiting FcεRI-mediated signaling.