A fusion protein of flagellin and ovalbumin suppresses the T(H)2 response and prevents murine intestinal allergy

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

来源：Journal of Allergy and Clinical Immunology, 2011, 128(6): 1340-U728.

DOI：10.1016/j.jaci.2011.07.036

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

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-gamma secretion by OVA-T-cell receptor transgenic CD4(+) T cells. Moreover, rflaA: OVA suppressed CD4(+) T cells derived from T(H)2-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. (J Allergy Clin Immunol 2011; 128: 1340-8.)

• 出版日期2011-12