Inhibition of allergen-specific IgE reactivity by a human Ig Fcgamma-Fcepsilon bifunctional fusion protein.
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 FcepsilonRI-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 anaphylaxis 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.


CONCLUSIONS
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.
Hart and Louis Lyon Laboratory, Division of Clinical Immunology and Allergy, Department of Medicine, University of California Los Angeles School of Medicine, CA 90095-1680, USA.
Ke
K
Zhang
Christopher L
CL
Kepley
Tetsuya
T
Terada
Daocheng
D
Zhu
Hector
H
Perez
Andrew
A
Saxon
D000485:Allergens / Q000276:immunology*; D000818:Animals; D001491:Basophils / Q000187:drug effects / Q000502:physiology; D015550:Cell Degranulation / Q000187:drug effects; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D008253:Macaca mulatta; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008925:Mites / Q000276:immunology; D017455:Receptors, IgE / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*
D000485:Allergens; D007141:Immunoglobulin Fc Fragments; D017455:Receptors, IgE; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D007073:Immunoglobulin E