Omalizumab inhibits acceleration of FcεRI-mediated responsiveness of immature human mast cells by immunoglobulin E.

Background: A large body of evidence has demonstrated that treatment with omalizumab is clinically effective for the management of moderate to severe allergic asthma, emphasizing the importance of IgE in the pathogenesis of allergic asthma. We hypothesized that IgE accelerates Fc epsilon RI-mediated responsiveness of "immature" human mast cells (MCs) and that omalizumab downregulates the acceleration. Objectives: To examine when MC progenitors acquired the ability to degranulate following Fc epsilon RI aggregation, whether IgE accelerates the responsiveness of immature MCs following Fc epsilon RI aggregation, and whether omalizumab regulates such an acceleration. Methods: Gene expression was examined using a microarray and quantitative reverse transcription polymerase chain reaction. Protein expression was investigated using FACS. Histamine release was examined using an EIA. Results: The time-course analysis of the mRNA expression of MC-related genes, including Fc epsilon RI, in Kit(+) sorted cells during the differentiation and histamine experiments revealed that the expression level of Fc epsilon RI in 5 week (w)-cultured MCs was not sufficient to induce degranulation following Fc epsilon RI aggregation but that 5 w-cultured MCs were fully responsive to calcium ionophore. By addition of IgE in culture medium Fc epsilon RI expression level and Fc epsilon RI-mediated histamine release of 5 w-cultured MC swere significantly increased compared with those without addition of IgE, whereas the expression level of tryptase and number of MCs was not affected. Omalizumab significantly inhibited IgE-dependent enhancement of Fc epsilon RI expression level and Fc epsilon RI-mediated histamine release. Conclusions: High levels of IgE in the microenvironment in vivo may upregulate the responsiveness of immature MCs to allergens. Omalizumab may inhibit the IgE-mediated responsiveness of not only mature MCs, but also immature MCs. (c) 2012 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.