Mechanisms of allergy and clinical immunologyA mouse Fcγ-Fcε protein that inhibits mast cells through activation of FcγRIIB, SH2 domain–containing inositol phosphatase 1, and SH2 domain–containing protein tyrosine phosphatases
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Cells and antibodies
Bone marrow cells from BALB/c or C57BL/6 mice were cultured for 5 to 12 weeks in complete medium (RPMI 1640; ATCC, Manassas, Va) containing 10% FBS (HyClone, Logan, Utah), 10 μg/mL gentamicin (Sigma-Aldrich, St Louis, Mo), 55 μmol/L β-mercaptoethanol (Invitrogen, Carlsbad, Calif), and recombinant IL-3 (10 ng/mL; R&D Systems, Minneapolis, Minn). FcγRIIB−/− mice on a BALB/c background were purchased from Taconic Farms (Hudson, NY). Animal experiments were approved by the Biogen Idec (San Diego,
mGE inhibits IgE-dependent BMMC activation
We generated a mouse homolog of the human GE2 fusion protein, designated mGE, consisting of mouse IgG2a-Fc and IgE-Fc regions linked by a glycine/serine peptide. By means of flow cytometry, mGE bound to To test mGE activity in vitro, BMMCs exclusively through FcεRI, which is consistent with the low affinity of FcγRIIB for monomeric IgG (data not shown). To test mGE activity in vitro, BMMCs were sensitized with IgE anti-TNP (10 μg/mL) in the presence of various concentrations of mGE. After
Discussion
We generated a mouse homolog of the previously investigated human GE2 protein designed to inhibit mast cell activation by cross-linking the inhibitory receptor FcγRIIB with FcεRI. mGE inhibitory activity was characterized on IgE-sensitized antigen-activated BMMCs and was confirmed to be similar to inhibition of human mast cells by human GE2.11 mGE was shown to inhibit BMMC activation at the level of mast cell release of both early- and late-phase mediators and required FcεRI binding. This is
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IgE and mast cells: The endogenous adjuvant
2020, Advances in ImmunologyCitation Excerpt :Consistent with this alternative theory, Shp-1 has been suggested to be the mediator of FcγRIIb's inhibitory effects in human basophils (Kepley et al., 2000; Saxon, Zhu, Zhang, Allen, & Kepley, 2004; Zhu, Kepley, Zhang, Zhang, & Saxon, 2002). Interestingly, this Fcɛ-Fcγ construct diminished phosphorylation of Syk as well as Erk, which could readily explain reductions in cytokine synthesis (Mertsching et al., 2008). Shp-1 is thought to dephosphorylate several early molecules in the FcɛRI signal transduction pathway, including Syk, LAT, SLP76 and the β/γ chains of FcɛRI itself (Nakata et al., 2008; Xie, Zhang, & Siraganian, 2000).
Emerging trends in bispecific antibody and scaffold protein therapeutics
2018, Current Opinion in Chemical EngineeringCitation Excerpt :Administration of immunosuppressives that may limit cytokine release is another consideration for this class of bispecifics. New mechanistic areas for bispecifics are also being considered that include targeting various cell types with enhanced specificity through affinity tuning [125,126], inducing cell death in specific tissues [29], inducing enhanced or novel activity through multi-epitope binding on the same target [58–60,100•], and in some cases by bringing receptors together, inducing novel activities [91•,127–129]. These novel bispecific mechanisms add a layer of complexity to each therapeutic compared to combination IgG therapy.
The high-affinity immunoglobulin e receptor as pharmacological target
2016, European Journal of PharmacologyCitation Excerpt :Co-aggregation of FcεRI with FcγRIIB was shown to inhibit FcεRI-mediated mast cell activation (Daeron et al., 1995; Tam et al., 2004) and human basophil activation (Cady et al., 2010; Cassard et al., 2012; Tam et al., 2004). More importantly, this mechanism was operative in various models of anaphylaxis in vivo in mice and monkeys (Mertsching et al., 2008; Strait et al., 2006; Zhu et al., 2005). Many different ways to co-aggregate FcγRIIB and FcεRI have been tested.
IgE and Mast Cells. The Endogenous Adjuvant.
2015, Advances in ImmunologyCitation Excerpt :Consistent with this alternative theory, Shp-1 has been suggested to be the mediator of FcγRIIb's inhibitory effects in human basophils (Kepley et al., 2000; Saxon, Zhu, Zhang, Allen, & Kepley, 2004; Zhu, Kepley, Zhang, Zhang, & Saxon, 2002). Interestingly, this Fcɛ–Fcγ construct diminished phosphorylation of Syk as well as Erk, which could readily explain reductions in cytokine synthesis (Mertsching et al., 2008). Shp-1 is thought to dephosphorylate several early molecules in FcɛRI signal transduction pathway, including Syk, LAT, SLP76, and the β/γ chains of FcɛRI itself (Nakata et al., 2008; Xie, Zhang, & Siraganian, 2000).
Transient gene expression of a mouse homolog of Fcε-Fcγ fusion protein for anti-allergic function assay
2011, Process Biochemistry
Disclosure of potential conflict of interest: E. Mertsching, H. Hess, K. Giza, E. Negrou, K. Hathaway, J. Chung, D. Perret, and M. R. Kehry are employed by Biogen Idec. L. Bafetti, S. Perper, and M. Shields were employed by Biogen Idec when this work was performed. A. Saxon has patent rights through his employment with the University of California.