title: Omalizumab inhibits acceleration of FcεRI-mediated responsiveness of immature human mast cells by immunoglobulin E.
abstract: 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 FcεRI-mediated responsiveness of "immature" human mast cells (MCs) and that omalizumab downregulates the acceleration.
  
  
  OBJECTIVE
  To examine when MC progenitors acquired the ability to degranulate following FcεRI aggregation, whether IgE accelerates the responsiveness of immature MCs following FcεRI 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 FcεRI, in Kit(+) sorted cells during the differentiation and histamine experiments revealed that the expression level of FcεRI in 5 week (w)-cultured MCs was not sufficient to induce degranulation following FcεRI aggregation but that 5 w-cultured MCs were fully responsive to calcium ionophore. By addition of IgE in culture medium FcεRI expression level and FcεRI-mediated histamine release of 5 w-cultured MCs were 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 FcεRI expression level and FcεRI-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.
authors.affiliation: Division of Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Science, Tokyo, Japan. okayama.yoshimichi@nihon-u.ac.jp
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Okayama
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kashiwakura
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sasaki-Sakamoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Noriko
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Ohmori
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kawakami
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D001249:Asthma / Q000473:pathology; D002478:Cells, Cultured; D015870:Gene Expression; D006636:Histamine Release; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology* / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D000069444:Omalizumab; D012333:RNA, Messenger / Q000096:biosynthesis; D017455:Receptors, IgE / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; C543355:FcepsilonRI alpha-chain, human; C543372:FcepsilonRI gamma-chain, human; C502447:MS4A2 protein, human; D012333:RNA, Messenger; D017455:Receptors, IgE; D000069444:Omalizumab; D007073:Immunoglobulin E