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

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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.

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