A novel human immunoglobulin Fc−Fc bifunctional fusion protein inhibits FcRI-mediated degranulation
Daocheng Zhu1, 3, Christopher L. Kepley2, 3, Min Zhang1, Ke Zhang1
& Andrew Saxon1
1
The Hart and Louise Lyon Laboratory, Division of Clinical Immunology/Allergy, Department of Medicine, University of California Los Angeles School of Medicine, Los Angeles, California, USA
2
Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
3
D.Z. and C.L.K. contributed equally to this study.
Human mast cells and basophils that express the high-affinity immunoglobulin E (IgE) receptor, Fc receptor 1 (FcRI), have key roles in allergic diseases. FcRI cross-linking stimulates the release of allergic mediators1. Mast cells and basophils co-express FcRIIb, a low affinity receptor containing an immunoreceptor tyrosine-based inhibitory motif and whose co-aggregation with FcRI can block FcRI-mediated reactivity2,
3,
4. Here we designed, expressed and tested the human basophil and mast-cell inhibitory function of a novel chimeric fusion protein, whose structure is Hinge-CH2-CH3-15aa linker-CH2-CH3-CH4. This Fc−Fc fusion protein was expressed as the predicted 140-D dimer that reacted with anti-human - and -chain specific antibodies. Fc−Fc bound to both human FcRI and FcRII. It also showed dose- and time-dependent inhibition of antigen-driven IgE-mediated histamine release from fresh human basophils sensitized with IgE directed against NIP (4-hydroxy-3-iodo-5-nitrophenylacetyl). This was associated with altered Syk signaling. The fusion protein also showed increased inhibition of human anti-NP (4-hydroxy-3-nitrophenylacetyl) and anti-dansyl IgE-mediated passive cutaneous anaphylaxis in transgenic mice expressing human FcRI. Our results show that this chimeric protein is able to form complexes with both FcRI and FcRII, and inhibit mast-cell and basophil function. This approach, using a Fc−Fc fusion protein to co-aggregate FcRI with a receptor containing an immunoreceptor tyrosine-based inhibition motif, has therapeutic potential in IgE- and FcRI-mediated diseases.
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REFERENCE Basophils Nature Encyclopaedia of Life Sciences Atopy and Asthma Nature Encyclopaedia of Life Sciences
−Fc
bifunctional fusion protein inhibits Fc
receptor 1 (Fc
RIIb, a low affinity receptor containing an immunoreceptor tyrosine-based inhibitory motif and whose co-aggregation with Fc
D dimer that reacted with anti-human 
. Our results show that this chimeric protein is able to form complexes with both Fc
