A 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

Mertsching, Elisabeth; Bafetti, L M; Hess, Henry; Perper, S.; Giza, Keith; Allen, Lisa Chan; Negrou, Ella; Hathaway, Karen; Hopp, Jennifer; Chung, Julie; Perret, Daniel; Shields, Michael J.; Saxon, Andrew; Kehry, Marilyn R.

doi:10.1016/j.jaci.2007.08.051

Cited by 33 publications

(20 citation statements)

References 25 publications

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“…Similarly, previous works that dealt with a bispecific Abs/fusion protein that inhibited MC activation by crosslinking FcRI with Fc␥RII did not report any interference with the Ag binding (26,28,30). Moreover, it was reported that this specific fusion protein did not exhibit any inhibitory effect on MC derived from Fc␥RIIB-deficient mice clearly demonstrating that inhibitory ITIM-recruited machinery, rather than a sterical inhibition of the activating receptor, was responsible for the inhibitory effects (31). Interestingly, CD300a was not able to inhibit HMC-1 survival, in accordance with previous reports showing similar outcome in other myeloid leukemias (32).…”

Section: Discussionmentioning

confidence: 56%

Suppression of Normal and Malignant Kit Signaling by a Bispecific Antibody Linking Kit with CD300a

Bachelet

Munitz

Berent-Maoz

et al. 2008

The Journal of Immunology

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Through its receptor Kit (CD117), stem cell factor (SCF) critically regulates human mast cell (MC) differentiation, survival, priming, and activation. The dominance of SCF in setting these parameters compels stringent contra-regulation to maintain a balanced MC phenotype. We have synthesized a library of bispecific Ab fragments to examine the effect of linking Kit with CD300a. In this study, we report that CD300a exerts a strong inhibitory effect on Kit-mediated SCF-induced signaling, consequently impairing MC differentiation, survival, and activation in vitro. This effect derives from Kit-mediated tyrosine phosphorylation of CD300a and recruitment of the SHIP-1 but not of SH2-containing protein phosphatase 1. CD300a inhibits the constitutive activation of the human leukemic HMC-1 cells but not their survival. Finally, CD300a abrogates the allergic reaction induced by SCF in a murine model of cutaneous anaphylaxis. Our findings highlight CD300a as a novel regulator of Kit in human MC and suggest roles for this receptor as a suppressor of Kit signaling in MC-related disorders.

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Section: Discussionmentioning

confidence: 56%

Suppression of Normal and Malignant Kit Signaling by a Bispecific Antibody Linking Kit with CD300a

Bachelet

Munitz

Berent-Maoz

et al. 2008

The Journal of Immunology

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“…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 Fcε-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 FcεRI signal transduction pathway, including Syk, LAT, SLP76, and the β/γ chains of FcεRI itself (Nakata et al, 2008;Xie, Zhang, & Siraganian, 2000).…”

Section: Fcγriib and Fcεri Signaling Interactionsmentioning

confidence: 88%

IgE and Mast Cells

Oettgen

Burton

2015

Advances in Immunology

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“…However, there is also evidence for another protective effect of allergen-specific IgG. It has been reported that concomitant binding of IgG and IgE antibodies to the same allergen may down-regulate effector cell responses through co-cross-linking of IgE and IgG receptors (Malbec and Daeron 2007;Mertsching et al 2008). These studies have been performed mainly in murine models whereas for human immunotherapy studies no evidence for down-regulation of effector cell activation by co-cross-linking has been found so far (Ejrnaes et al 2006).…”

Section: Beneficial Role Of Allergen-specific Blocking Igg Antibodiesmentioning

confidence: 99%

Passive Immunization with Allergen-Specific Antibodies

Flicker

Gadermaier

Madritsch

et al. 2011

Vaccines Against Allergies

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The induction of allergen-specific IgG antibodies has been identified as a major mechanism responsible for the reduction of allergic inflammation in allergic patients treated by allergen-specific immunotherapy. Several studies suggest that allergen-specific IgG antibodies induced by vaccination with allergens block mast cell and basophil degranulation, IgE-facilitated allergen presentation to T cells and IgE production. The availability of recombinant allergens and technologies for the production of recombinant human antibodies allows engineering of allergen-specific antibodies which can be used for passive immunization (i.e., therapy) and eventually for the prevention of allergy (i.e., prophylaxis). This chapter summarizes data supporting the possible use of allergen-specific antibodies for treatment and prophylaxis. Finally, concrete approaches for the treatment and prevention of allergy based on blocking antibodies are envisioned.

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A 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

Cited by 33 publications

References 25 publications

Suppression of Normal and Malignant Kit Signaling by a Bispecific Antibody Linking Kit with CD300a

Suppression of Normal and Malignant Kit Signaling by a Bispecific Antibody Linking Kit with CD300a

IgE and Mast Cells

Passive Immunization with Allergen-Specific Antibodies

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