BTK-inhibition is a potent approach to block IgE-mediated histamine release in human basophils

Abstract

Background

Recent data suggest that Bruton′s tyrosine kinase (BTK) is an emerging therapeutic target in IgE receptor (IgER) cross-linked basophils.

Methods

We examined the effects of four BTK inhibitors (ibrutinib, dasatinib, AVL-292, CNX-774) on IgE-dependent activation and histamine release in blood basophils obtained from allergic patients (n=11) and non-allergic donors (n=5). In addition, we examined the effects of these drugs on the growth of the human basophil cell line KU812 and the human mast cell line HMC-1.

Results

All four BTK blockers were found to inhibit anti-IgE-induced histamine release from basophils in non-allergic subjects and allergen-induced histamine liberation from basophils in allergic donors. Drug effects on allergen-induced histamine release were dose-dependent, with IC₅₀ values ranging between 0.001 and 0.5 μM, and the following rank-order of potency: ibrutinib>AVL-292> dasatinib>CNX-774. The basophil-targeting effect of ibrutinib was confirmed by demonstrating that IgE-dependent histamine release in ex vivo blood basophils is largely suppressed in a leukemia patient treated with ibrutinib. Dasatinib and ibrutinib were also found to counteract anti-IgE-induced and allergen-induced upregulation of CD13, CD63, CD164, and CD203c on basophils, whereas AVL-292 and CNX-774 showed no significant effects. Whereas dasatinib and CNX-774 were found to inhibit the growth of HMC-1 cells and KU812 cells, no substantial effects were seen with ibrutinib or AVL-292.

Conclusions

BTK-targeting drugs are potent inhibitors of IgE-dependent histamine release in human basophils. The clinical value of BTK inhibition in the context of allergic diseases remains to be determined.

This article is protected by copyright. All rights reserved.

http://ift.tt/2o4OXpA