A fusion protein of flagellin and ovalbumin suppresses the TH2 response and prevents murine intestinal allergy

Stefan Schülke; Manja Burggraf; Zoe Waibler; Andrea Wangorsch; Sonja Wolfheimer; Ulrich Kalinke; Stefan Vieths; Masako Toda; Stephan Scheurer

doi:10.1016/j.jaci.2011.07.036

A fusion protein of flagellin and ovalbumin suppresses the T_H2 response and prevents murine intestinal allergy

Stefan Schülke, Manja Burggraf, Zoe Waibler, Andrea Wangorsch, Sonja Wolfheimer, Ulrich Kalinke, Stefan Vieths, Masako Toda, Stephan Scheurer

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

Abstract

Background: The Toll-like receptor (TLR) 5 agonist flagellin is associated with immunomodulatory functions. Objective: We sought to investigate whether Listeria monocytogenes-derived flagellin A (flaA) can modulate ovalbumin (OVA)-specific T-cell responses and prevent OVA-induced intestinal allergy. Methods: Bone marrow-derived myeloid dendritic cells from BALB/c, C57BL/6, or TLR signaling-deficient (MyD88^-/-) mice were stimulated with rOVA, rflaA, rflaA plus rOVA, or a recombinant fusion protein consisting of rflaA and rOVA (rflaA:OVA). The immunomodulating properties of rflaA plus rOVA and rflaA:OVA were investigated by means of DC-T-cell coculture with CD4⁺ T cells from OVA-T-cell receptor transgenic or OVA/alum-immunized mice. rflaA:OVA was applied as a prophylactic and therapeutic vaccine in a murine model of intestinal allergy. Results: rflaA:OVA induced upregulation of TLR5 and dose-dependent IL-6 and IL-10 secretion by myeloid dendritic cells. IL-10 contributed to repressing IL-4 and IFN-γ secretion by OVA-T-cell receptor transgenic CD4⁺ T cells. Moreover, rflaA:OVA suppressed CD4 ⁺ T cells derived from T_H2-biased mice on OVA/alum immunization. In a murine model of intestinal allergy, prophylactic vaccination with rflaA:OVA reduced T-cell activation. Protection from intestinal allergy included suppression of OVA-specific IgE while inducing OVA-specific IgG _2a. Equimolar amounts of rflaA or rOVA provided alone or as a mixture did not have comparable effects. Moreover, therapeutic vaccination was shown to reduce allergic symptoms and T-cell activation in the spleen. Conclusion: The rflaA:OVA fusion protein showed strong TLR-mediated immunomodulating capacities probably attributed by the proximity of adjuvant and allergen, leading to the prevention of intestinal allergy in a murine disease model. Therefore recombinant flaA:allergen fusion proteins are promising vaccine candidates for intervention in patients with IgE-mediated allergy.

Original language	English
Pages (from-to)	1340-1348.e12
Journal	Journal of Allergy and Clinical Immunology
Volume	128
Issue number	6
DOIs	https://doi.org/10.1016/j.jaci.2011.07.036
Publication status	Published - 2011 Dec
Externally published	Yes

Keywords

Flagellin
Toll-like receptor 5
allergen vaccine
dendritic cell
intestinal allergy

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jaci.2011.07.036

Cite this

@article{e17a752b199a4a8c92133601f28756d2,

title = "A fusion protein of flagellin and ovalbumin suppresses the TH2 response and prevents murine intestinal allergy",

abstract = "Background: The Toll-like receptor (TLR) 5 agonist flagellin is associated with immunomodulatory functions. Objective: We sought to investigate whether Listeria monocytogenes-derived flagellin A (flaA) can modulate ovalbumin (OVA)-specific T-cell responses and prevent OVA-induced intestinal allergy. Methods: Bone marrow-derived myeloid dendritic cells from BALB/c, C57BL/6, or TLR signaling-deficient (MyD88-/-) mice were stimulated with rOVA, rflaA, rflaA plus rOVA, or a recombinant fusion protein consisting of rflaA and rOVA (rflaA:OVA). The immunomodulating properties of rflaA plus rOVA and rflaA:OVA were investigated by means of DC-T-cell coculture with CD4+ T cells from OVA-T-cell receptor transgenic or OVA/alum-immunized mice. rflaA:OVA was applied as a prophylactic and therapeutic vaccine in a murine model of intestinal allergy. Results: rflaA:OVA induced upregulation of TLR5 and dose-dependent IL-6 and IL-10 secretion by myeloid dendritic cells. IL-10 contributed to repressing IL-4 and IFN-γ secretion by OVA-T-cell receptor transgenic CD4+ T cells. Moreover, rflaA:OVA suppressed CD4 + T cells derived from TH2-biased mice on OVA/alum immunization. In a murine model of intestinal allergy, prophylactic vaccination with rflaA:OVA reduced T-cell activation. Protection from intestinal allergy included suppression of OVA-specific IgE while inducing OVA-specific IgG 2a. Equimolar amounts of rflaA or rOVA provided alone or as a mixture did not have comparable effects. Moreover, therapeutic vaccination was shown to reduce allergic symptoms and T-cell activation in the spleen. Conclusion: The rflaA:OVA fusion protein showed strong TLR-mediated immunomodulating capacities probably attributed by the proximity of adjuvant and allergen, leading to the prevention of intestinal allergy in a murine disease model. Therefore recombinant flaA:allergen fusion proteins are promising vaccine candidates for intervention in patients with IgE-mediated allergy.",

keywords = "Flagellin, Toll-like receptor 5, allergen vaccine, dendritic cell, intestinal allergy",

author = "Stefan Sch{\"u}lke and Manja Burggraf and Zoe Waibler and Andrea Wangorsch and Sonja Wolfheimer and Ulrich Kalinke and Stefan Vieths and Masako Toda and Stephan Scheurer",

note = "Funding Information: Supported by the DFG ( SCHE637/3 ). Funding Information: Disclosure of potential conflict of interest: S. Vieths is an Associate at the Institute for Product Quality, Berlin, Germany; has received honoraria from the Food Allergy Resource and Research Program (Lincoln, Neb) and Fresenius Academy (Dortmund, Germany); has received research support from the German Federal Ministry of Health, the German Research Foundation , the Research Fund of the German Food Industry, Monsanto Company, Pioneer Hi-Bred International, the Food Allergy Research & Resource Program, the European Directorate for the Quality of Medicines and Health Care , and the German Federal Ministry for Education and Research; is a member of the European Academy of Allergy and Clinical Immunology (EAACI) Executive Committee; is Chairman of the International Union of Immunological Societies (IUIS) Allergen Standardization Subcommittee; is Secretary of the International Union of Immunological Societies (IUIS) Allergen Nomenclature Subcommittee; is a registered expert with the European Agency for the Evaluation of Medicinal Products and the European Pharmacopoeia Commission; is Chairman of the CEN (European Committee for Standardization) Technical Committee 275 Working Group 12 “Food Allergens”; and is a member of the German Society for Allergy and Clinical Immunology Food Allergy Working Group. The rest of the authors have declared that they have no conflict of interest. ",

year = "2011",

month = dec,

doi = "10.1016/j.jaci.2011.07.036",

language = "English",

volume = "128",

pages = "1340--1348.e12",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "6",

}

TY - JOUR

T1 - A fusion protein of flagellin and ovalbumin suppresses the TH2 response and prevents murine intestinal allergy

AU - Schülke, Stefan

AU - Burggraf, Manja

AU - Waibler, Zoe

AU - Wangorsch, Andrea

AU - Wolfheimer, Sonja

AU - Kalinke, Ulrich

AU - Vieths, Stefan

AU - Toda, Masako

AU - Scheurer, Stephan

N1 - Funding Information: Supported by the DFG ( SCHE637/3 ). Funding Information: Disclosure of potential conflict of interest: S. Vieths is an Associate at the Institute for Product Quality, Berlin, Germany; has received honoraria from the Food Allergy Resource and Research Program (Lincoln, Neb) and Fresenius Academy (Dortmund, Germany); has received research support from the German Federal Ministry of Health, the German Research Foundation , the Research Fund of the German Food Industry, Monsanto Company, Pioneer Hi-Bred International, the Food Allergy Research & Resource Program, the European Directorate for the Quality of Medicines and Health Care , and the German Federal Ministry for Education and Research; is a member of the European Academy of Allergy and Clinical Immunology (EAACI) Executive Committee; is Chairman of the International Union of Immunological Societies (IUIS) Allergen Standardization Subcommittee; is Secretary of the International Union of Immunological Societies (IUIS) Allergen Nomenclature Subcommittee; is a registered expert with the European Agency for the Evaluation of Medicinal Products and the European Pharmacopoeia Commission; is Chairman of the CEN (European Committee for Standardization) Technical Committee 275 Working Group 12 “Food Allergens”; and is a member of the German Society for Allergy and Clinical Immunology Food Allergy Working Group. The rest of the authors have declared that they have no conflict of interest.

PY - 2011/12

Y1 - 2011/12

N2 - Background: The Toll-like receptor (TLR) 5 agonist flagellin is associated with immunomodulatory functions. Objective: We sought to investigate whether Listeria monocytogenes-derived flagellin A (flaA) can modulate ovalbumin (OVA)-specific T-cell responses and prevent OVA-induced intestinal allergy. Methods: Bone marrow-derived myeloid dendritic cells from BALB/c, C57BL/6, or TLR signaling-deficient (MyD88-/-) mice were stimulated with rOVA, rflaA, rflaA plus rOVA, or a recombinant fusion protein consisting of rflaA and rOVA (rflaA:OVA). The immunomodulating properties of rflaA plus rOVA and rflaA:OVA were investigated by means of DC-T-cell coculture with CD4+ T cells from OVA-T-cell receptor transgenic or OVA/alum-immunized mice. rflaA:OVA was applied as a prophylactic and therapeutic vaccine in a murine model of intestinal allergy. Results: rflaA:OVA induced upregulation of TLR5 and dose-dependent IL-6 and IL-10 secretion by myeloid dendritic cells. IL-10 contributed to repressing IL-4 and IFN-γ secretion by OVA-T-cell receptor transgenic CD4+ T cells. Moreover, rflaA:OVA suppressed CD4 + T cells derived from TH2-biased mice on OVA/alum immunization. In a murine model of intestinal allergy, prophylactic vaccination with rflaA:OVA reduced T-cell activation. Protection from intestinal allergy included suppression of OVA-specific IgE while inducing OVA-specific IgG 2a. Equimolar amounts of rflaA or rOVA provided alone or as a mixture did not have comparable effects. Moreover, therapeutic vaccination was shown to reduce allergic symptoms and T-cell activation in the spleen. Conclusion: The rflaA:OVA fusion protein showed strong TLR-mediated immunomodulating capacities probably attributed by the proximity of adjuvant and allergen, leading to the prevention of intestinal allergy in a murine disease model. Therefore recombinant flaA:allergen fusion proteins are promising vaccine candidates for intervention in patients with IgE-mediated allergy.

AB - Background: The Toll-like receptor (TLR) 5 agonist flagellin is associated with immunomodulatory functions. Objective: We sought to investigate whether Listeria monocytogenes-derived flagellin A (flaA) can modulate ovalbumin (OVA)-specific T-cell responses and prevent OVA-induced intestinal allergy. Methods: Bone marrow-derived myeloid dendritic cells from BALB/c, C57BL/6, or TLR signaling-deficient (MyD88-/-) mice were stimulated with rOVA, rflaA, rflaA plus rOVA, or a recombinant fusion protein consisting of rflaA and rOVA (rflaA:OVA). The immunomodulating properties of rflaA plus rOVA and rflaA:OVA were investigated by means of DC-T-cell coculture with CD4+ T cells from OVA-T-cell receptor transgenic or OVA/alum-immunized mice. rflaA:OVA was applied as a prophylactic and therapeutic vaccine in a murine model of intestinal allergy. Results: rflaA:OVA induced upregulation of TLR5 and dose-dependent IL-6 and IL-10 secretion by myeloid dendritic cells. IL-10 contributed to repressing IL-4 and IFN-γ secretion by OVA-T-cell receptor transgenic CD4+ T cells. Moreover, rflaA:OVA suppressed CD4 + T cells derived from TH2-biased mice on OVA/alum immunization. In a murine model of intestinal allergy, prophylactic vaccination with rflaA:OVA reduced T-cell activation. Protection from intestinal allergy included suppression of OVA-specific IgE while inducing OVA-specific IgG 2a. Equimolar amounts of rflaA or rOVA provided alone or as a mixture did not have comparable effects. Moreover, therapeutic vaccination was shown to reduce allergic symptoms and T-cell activation in the spleen. Conclusion: The rflaA:OVA fusion protein showed strong TLR-mediated immunomodulating capacities probably attributed by the proximity of adjuvant and allergen, leading to the prevention of intestinal allergy in a murine disease model. Therefore recombinant flaA:allergen fusion proteins are promising vaccine candidates for intervention in patients with IgE-mediated allergy.

KW - Flagellin

KW - Toll-like receptor 5

KW - allergen vaccine

KW - dendritic cell

KW - intestinal allergy

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