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

Abstract

BackgroundRecent data suggest that Bruton's tyrosine kinase (BTK) is an emerging therapeutic target in IgE receptor (IgER)‐cross‐linked basophils.MethodsWe examined the effects of four BTK inhibitors (ibrutinib, dasatinib, AVL‐292, and CNX‐774) on IgE‐dependent activation and histamine release in blood basophils obtained from allergic patients (n=11) and nonallergic 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.ResultsAll four BTK blockers were found to inhibit anti‐IgE‐induced histamine release from basophils in nonallergic subjects and allergen‐induced histamine liberation from basophils in allergic donors. Drug effects on allergen‐induced histamine release were dose dependent, with IC 50 values ranging between 0.001 and 0.5 μmol/L, 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.

Effects of ibrutinib on proliferation and histamine release in canine neoplastic mast cells

“…Ibrutinib has recently been shown to counteract IgE‐dependent activation of human BAs . To examine whether ibrutinib exerts inhibitory effects on IgE‐dependent histamine release in canine neoplastic MCs, we performed experiments using NI‐1 cells, known to express a functional IgE receptor and primary mastocytoma cells.…”

“…Since concentrations required for blocking histamine release were significantly lower than for blocking proliferation and survival, ibrutinib may also have clinical implications for other IgE‐dependent diseases in dogs, such as canine atopic dermatitis or food allergies . Our findings are reinforced by previous data showing that BTK is expressed in human BAs and MCs and that BTK inhibition by ibrutinib is associated with reduced IgE‐dependent mediator release in these cells …”

“…Furthermore, BTK has been described to play an important role as a target in the downstream pathway of IgE receptor‐cross‐linked human basophils (BAs) and MCs . More recently, studies published by our and other groups have identified ibrutinib as a potent blocker of IgE‐dependent activation and histamine release in human BAs . However, only few reports exist about the in vitro and in vivo effects of ibrutinib in dogs.…”

Effects of BTK signalling in pathogenic microorganism infections

“…For example, in rheumatoid arthritis, Btk overexpression occurs, and inhibition of Btk signalling is an effective approach for its treatment . Similarly, Btk is required for FcεRI‐mediated activation and histamine release in mast cells and basophils, and the application of Btk inhibitors greatly improves the outcome of allergy diseases . Although there are some studies on the roles of Btk signalling in microbial infections, they are still lacking a comprehensible and in‐depth summary, and the results are uncertain and even conflicting.…”

“…7 Similarly, Btk is required for FcεRI-mediated activation and histamine release in mast cells and basophils, and the application of Btk inhibitors greatly improves the outcome of allergy diseases. 6,8 Although there are some studies on the roles of Btk signalling in microbial infections, they are still lacking a comprehensible and in-depth summary, and the results are uncertain and even conflicting. Therefore, we present the current knowledge on the effects of Btk signalling in pathogenic microorganism infections, including mainly those caused by viruses, bacteria, fungi and parasites.…”