A fusion protein of flagellin and ovalbumin suppresses the TH2 response and prevents murine intestinal allergy - 30/11/11
Corresponding author: Stephan Scheurer, PhD, Paul-Ehrlich-Institut, Division of Allergology, Section Recombinant Allergen Therapeutics, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany.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 IgG2a. 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.
Le texte complet de cet article est disponible en PDF.Key words : Flagellin, Toll-like receptor 5, allergen vaccine, dendritic cell, intestinal allergy
Abbreviations used : CN, DC, EW, flaA, mDC, OVA, OVA/A, TCR, TLR, Treg
Plan
| Supported by the DFG (SCHE637/3). |
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| 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. |
Vol 128 - N° 6
P. 1340 - décembre 2011 Retour au numéro
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