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A heterobivalent ligand inhibits mast cell degranulation via selective inhibition of allergen-IgE interactions in vivo.

ABSTRACT: Current treatments for allergies include epinephrine and antihistamines, which treat the symptoms after an allergic response has taken place; steroids, which result in local and systemic immune suppression; and IgE-depleting therapies, which can be used only for a narrow range of clinical IgE titers. The limitations of current treatments motivated the design of a heterobivalent inhibitor (HBI) of IgE-mediated allergic responses that selectively inhibits allergen-IgE interactions, thereby preventing IgE clustering and mast cell degranulation. The HBI was designed to simultaneously target the allergen binding site and the adjacent conserved nucleotide binding site (NBS) found on the Fab of IgE Abs. The bivalent targeting was accomplished by linking a hapten to an NBS ligand with an ethylene glycol linker. The hapten moiety of HBI enables selective targeting of a specific IgE, whereas the NBS ligand enhances avidity for the IgE. Simultaneous bivalent binding to both sites provided HBI with 120-fold enhancement in avidity for the target IgE compared with the monovalent hapten. The increased avidity for IgE made HBI a potent inhibitor of mast cell degranulation in the rat basophilic leukemia mast cell model, in the passive cutaneous anaphylaxis mouse model of allergy, and in mice sensitized to the model allergen. In addition, HBI did not have any observable systemic toxic effects even at elevated doses. Taken together, these results establish the HBI design as a broadly applicable platform with therapeutic potential for the targeted and selective inhibition of IgE-mediated allergic responses, including food, environmental, and drug allergies.

SUBMITTER: Handlogten MW

PROVIDER: S-EPMC3951166 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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A heterobivalent ligand inhibits mast cell degranulation via selective inhibition of allergen-IgE interactions in vivo.

Handlogten Michael W MW Serezani Ana P AP Sinn Anthony L AL Pollok Karen E KE Kaplan Mark H MH Bilgicer Basar B

Journal of immunology (Baltimore, Md. : 1950) 20140131 5

Current treatments for allergies include epinephrine and antihistamines, which treat the symptoms after an allergic response has taken place; steroids, which result in local and systemic immune suppression; and IgE-depleting therapies, which can be used only for a narrow range of clinical IgE titers. The limitations of current treatments motivated the design of a heterobivalent inhibitor (HBI) of IgE-mediated allergic responses that selectively inhibits allergen-IgE interactions, thereby prevent ...[more]

PMID: 24489096

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Project description:Mast cells and basophils are central players in allergic reactions triggered by immunoglobulin E (IgE). They have intracellular granules containing allergic mediators (e.g., histamine, serotonin, inflammatory cytokines, proteases and ?-hexosaminidase), and stimulation by IgE-allergen complex leads to the release of such allergic mediators from the granules, that is, degranulation. Mast cells are residents of mucosal surfaces, including those of nasal and oral cavities, and play an important role in the innate defense system. Members of the mitis group streptococci such as Streptococcus oralis, are primary colonizers of the human oral cavity. They produce hydrogen peroxide (H2O2) as a by-product of sugar metabolism. In this study, we investigated the effects of streptococcal infection on RBL-2H3 mast cell/basophil cell line. Infection by oral streptococci did not induce degranulation of the cells. Stimulation of the RBL-2H3 cells with anti-dinitrophenol (DNP) IgE and DNP-conjugated human serum albumin triggers degranulation with the release of ?-hexosaminidase. We found that S. oralis and other mitis group streptococci inhibited the IgE-triggered degranulation of RBL-2H3 cells. Since mitis group streptococci produce H2O2, we examined the effect of S. oralis mutant strain deficient in producing H2O2, and found that they lost the ability to suppress the degranulation. Moreover, H2O2 alone inhibited the IgE-induced degranulation. Subsequent analysis suggested that the inhibition of degranulation was related to the cytotoxicity of streptococcal H2O2. Activated RBL-2H3 cells produce interleukin-4 (IL-4); however, IL-4 production was not induced by streptococcal H2O2. Furthermore, an in vivo study using the murine pollen-induced allergic rhinitis model suggested that the streptococcal H2O2 reduces nasal allergic reaction. These findings reveal that H2O2 produced by oral mitis group streptococci inhibits IgE-stimulated degranulation by inducing cell death. Consequently, streptococcal H2O2 can be considered to modulate the allergic reaction in mucosal surfaces.

Dataset Information

A heterobivalent ligand inhibits mast cell degranulation via selective inhibition of allergen-IgE interactions in vivo.

Publications

A heterobivalent ligand inhibits mast cell degranulation via selective inhibition of allergen-IgE interactions in vivo.

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