Rapid polyclonal desensitization with antibodies to IgE and FcεRIα

Abstract

Background Rapid desensitization,a procedure in which individuals allergic to an antigen are treated at short intervals with increasing doses of that antigen until they tolerate a large dose, is an effective, but risky way to induce temporary tolerance. Objective To determine whether this approach can be adapted to suppress all IgE-mediated in mice by injecting serially increasing doses of monoclonal antibodies (mAbs) to IgE or FcεRIα. Methods Active and passive models of antigen- and anti-IgE mAb-induced IgE-mediated anaphylaxis were used. Mice were desensitized with serially increasing doses of anti-IgE mAb, anti-FcεRIα mAb or antigen. Development of shock (hypothermia), histamine and mast cell protease release, cytokine secretion, calcium flux and changes in cell number and FcεRI and IgE expression were evaluated. Results Rapid desensitization with anti-IgE mAb suppressed IgE-mediated immediate hypersensitivity; however, some mice developed mild anaphylaxis during desensitization. Rapid desensitization with anti-FcεRIα mAb that only binds FcεRI that is not occupied by IgE suppressed both active and passive IgE-mediated anaphylaxis without inducing disease. It quickly, but temporarily, suppressed IgE-mediated anaphylaxis by decreasing mast cell signaling through FcεRI, then slowly slowlyinduced longer lasting mast cell unresponsiveness by removing membrane FcεRI. Rapid desensitization with anti-FcεRIα mAb was safer and longer-lasting than rapid desensitization with antigen. Conclusion A rapid desensitization approach with anti-FcεRIα mAb safely desensitizes mice to IgE-mediated anaphylaxis by inducing mast cell anergy and later, removing all mast cell IgE. Rapid desensitization with an anti-human FcεRIα mAb may be able to prevent human IgE-mediated anaphylaxis.

Immunoglobulin E Signal Inhibition during Allergen Ingestion Leads to Reversal of Established Food Allergy and Induction of Regulatory T Cells

“…In order to use these antibodies in the peanut model we had to mitigate this effect. Taking advantage of a rush desensitization protocol developed by Khodoun and colleagues (Khodoun et al, 2013), we treated mice with anti-IgE in a four-day build-up prior to the first exposure to peanut. Neutralization of IgE mimicked genetic deletion of IgE, rendering the IL-4rα mutant mice resistant to anaphylactic reactions (Figure 2A).…”

Mast cell desensitization inhibits calcium flux and aberrantly remodels actin

“…Our own studies titrating BMMCs with various dilutions of IgE showed that maximal degranulation in response to Ag could be induced even with relatively low amounts of IgE bound to receptors (Supplemental Figure 1). Additionally, Khodoun et al achieved desensitization of MCs using antibodies against FcεRI, without causing complete internalization of surface receptors, once again suggesting that complete depletion of surface FcεRI was not necessary for desensitization (44). Indeed, while we observed IgE internalization during Ag activation and desensitization, this typically was not complete, as Ag-activated cells still had approximately 50% of baseline cell surface IgE, whereas desensitized cells had approximately 70% of baseline cell surface IgE (Figure 2D).…”

The future of biologics: Applications for food allergy

“…167 However, when escalating doses of anti-IgE or anti-FcεRIα were administered, rapid desensitization was induced that prevented anaphylaxis. 168 Rapid desensitization with anti-FcεRIα was found to promote mast cell anergy and also to quickly remove FcεRI-bound IgE from mast cells, thus preventing any adverse effects mediated by IgE already bound by FcεRIα before the rapid desensitization protocol was begun. However, this induced mast cell anergy was short-lived.…”