Dataset Information

Blockade of peanut allergy with a novel Ara h 2-Fc? fusion protein in mice.

ABSTRACT:

Background

Conventional immunotherapy for peanut allergy using crude peanut extracts is not recommended because of the unacceptably high risk of anaphylaxis. Allergen-specific immunotherapy is not currently undertaken for peanut allergy.

Objectives

The objective of this study was to develop a novel peanut-human fusion protein to block peanut-induced anaphylaxis.

Methods

We genetically designed and expressed a novel plant-human fusion protein composed of the major peanut allergen Ara h 2 and human IgG Fc?1. We tested the Ara h 2-Fc? fusion protein (AHG2)'s function in purified human basophils. Transgenic mice expressing human Fc?RI? and a murine peanut allergy model were used.

Results

AHG2 inhibited histamine release induced by whole peanut extract (WPE) from basophils of patients with peanut allergy, whereas the fusion protein itself did not induce mediator release. AHG2 inhibited the WPE-induced, peanut-specific, IgE-mediated passive cutaneous anaphylaxis in hFc?RI? transgenic mice. AHG2 also significantly inhibited acute anaphylactic reactivity, including the prototypical decrease in body temperature in WPE-sensitized mice challenged with crude peanut extract. Histologic evaluation of the airways showed that AHG2 decreased peanut-induced inflammation, whereas the fusion protein itself did not induce airway inflammation in peanut-sensitized mice. AHG2 did not exert an inhibitory effect in mice lacking Fc?RII.

Conclusion

AHG2 inhibited peanut-specific IgE-mediated allergic reactions in vitro and in vivo. Linking specific peanut allergen to Fc? can provide a new approach for the allergen immunotherapy of peanut allergy.

SUBMITTER: Liu Y

PROVIDER: S-EPMC3651897 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Publications

Blockade of peanut allergy with a novel Ara h 2-Fcγ fusion protein in mice.

Liu Yu Y Sun Yongtao Y Chang Lee-Jah LJ Li Newton N Li Huabin H Yu Yanni Y Bryce Paul J PJ Grammer Leslie C LC Schleimer Robert P RP Zhu Daocheng D

The Journal of allergy and clinical immunology 20121127 1

<h4>Background</h4>Conventional immunotherapy for peanut allergy using crude peanut extracts is not recommended because of the unacceptably high risk of anaphylaxis. Allergen-specific immunotherapy is not currently undertaken for peanut allergy.<h4>Objectives</h4>The objective of this study was to develop a novel peanut-human fusion protein to block peanut-induced anaphylaxis.<h4>Methods</h4>We genetically designed and expressed a novel plant-human fusion protein composed of the major peanut all ...[more]

PMID: 23199607

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Project description:IntroductionAs the only market-authorized allergen immunotherapy (AIT) for peanut allergy is accompanied by a high risk of side effects and mainly induces robust desensitization without sustained efficacy, novel treatment options are required. Peanut-specific plant-derived eBioparticles (eBPs) surface expressing Ara h 2 at high density have been shown to be very hypoallergenic. Here, we assessed the dendritic cell (DC)-activating and T cell polarization capacity of these peanut-specific eBPs.MethodsRoute and kinetics of eBP uptake were studied by (imaging) flow cytometry using monocyte-derived DCs incubated with fluorescently-labelled Ara h 2 eBPs or natural Ara h 2 (nAra h 2) in the presence or absence of inhibitors that block pathways involved in macropinocytosis, phagocytosis, and/or receptor-mediated uptake. DC activation was monitored by flow cytometry (maturation marker expression) and ELISA (cytokine production). T cell polarization was assessed by co-culturing DCs exposed to Ara h 2 eBPs or nAra h 2 with naïve CD4+ T cells, followed by flow cytometry assessment of intracellular IFNγ+ (Th1) and IL-13+ (Th2), and CD25+CD127-Foxp3+ regulatory T cells (Tregs). The suppressive activity of Tregs was tested using a suppressor assay.ResultsAra h 2 eBPs were taken up by DCs through actin-dependent pathways. They activated DCs demonstrated by an induced expression of CD83 and CD86, and production of TNFα, IL-6, and IL-10. eBP-treated DCs polarized naïve CD4+ T cells towards Th1 cells, while reducing Th2 cell development. Furthermore, eBP-treated DCs induced reduced the frequency of Foxp3+ Tregs but did not significantly affect T cell IL-10 production or T cells with suppressive capacity. In contrast, DC activation and Th1 cell polarization were not observed for nAra h 2.ConclusionAra h 2 eBPs activate DCs that subsequently promote Th1 cell polarization and reduce Th2 cell polarization. These characteristics mark Ara h 2 eBPs as a promising novel candidate for peanut AIT.