Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 114, Issue 2, Pages 321-327Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2004.03.058
Keywords
allergen; IgE; Fc epsilon RI; anaphylaxis; fusion protein; immunotherapy; degranulution; mast cells; basophils; transgenic mouse
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Funding
- NIAID NIH HHS [AI11521, AI28697, AI53257] Funding Source: Medline
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Background: Coaggregating FcepsilonRI with FcgammaRII receptors holds great potential for treatment of IgE-mediated disease by inhibiting FcepsilonRI signaling. We have previously shown that an Fcgamma-Fcepsilon fusion protein, human IgG-IgE Fc fusion protein (GE2), could inhibit FeepsilonRI-mediated mediator releases in vitro and in vivo. Objective: We sought to test whether GE2 was capable of blocking mediator release from FcepsilonRI cells sensitized with IgE in vivo or in vitro before exposure to GE2, a critical feature for GE2 to be clinically applicable. Methods: GE2 was tested for its ability to inhibit Fel d 1-induced mediator release from human blood basophils from subjects with cat allergy, human lung-derived mast cells, human FcepsilonRIalpha transgenic mice sensitized with human cat allergic serum, and rhesus; monkeys naturally allergic to the dust mite Dermatophagoides farinae. Results: Basophils from subjects with cat allergy and lung mast cells degranulate when challenged with Fel d 1 and anti-IgE, respectively. GE2 itself did not induce mediator release but strongly blocked this Fel d 1- and anti-IgE-driven mediator release. GE2 was able to block Fel d 1-driven passive cutaneous anaphylaxis at skin sites sensitized with human serum from subjects with cat allergy in human FcepsilonRIalpha transgenic mice, but by itself, GE2 did not induce a passive cutaneous anaphyiaxis reaction. Finally, GE2 markedly inhibited skin test reactivity to D farinae in monkeys naturally allergic to this allergen, with complete inhibition being observed at 125 ng. Conclusion: GE2 is able to successfully compete for FcepsilonRs and FcgammaRs on cells presensitized in vitro and in vivo and lead to inhibition of IgE-mediated reactivity through coaggregation of FcepsilonRI with FcgammaRII.
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