Toll-like receptor 2 agonist Pam3CSK4 enhances the induction of antigen-specific tolerance via the sublingual route

Authors


Correspondence:
Philippe Moingeon, Research and Development, Stallergènes SA, 6 Rue Alexis de Tocqueville, 92183 Antony, Cedex, France.
E-mail: pmoingeon@stallergenes.fr

Summary

Background Sublingual immunotherapy (SLIT) has been established in humans as a safe and efficacious treatment for type I respiratory allergies.

Objective In this study, we compared three Toll-like receptor (TLR) 2 ligands (Pam3CSK4, Porphyromonas gingivalis lipopolysaccharide and lipoteichoic acid) as potential adjuvants for sublingual allergy vaccines.

Methods These molecules were tested in co-cultures of adjuvant-pre-treated dendritic cells (DCs) with murine naïve CD4+ T lymphocytes. Patterns of cytokine production, phenotype, proliferation and gene expression were analysed by ELISA, cytofluorometry and quantitative PCR, respectively. TLR2 ligands were subsequently tested in a model of SLIT in BALB/c mice sensitized with ovalbumin (OVA).

Results Among the three TLR2 ligands tested, the synthetic lipopeptide Pam3CSK4 is the most potent inducer of IL-12p35 and IL-10 gene expression in murine bone marrow-derived DCs, as well as in purified oral myeloid DCs. Only Pam3CSK4-treated DCs induce IFN-γ and IL-10 secretion by naïve CD4+ T cells. Sublingual administration of Pam3CSK4 together with the antigen in BALB/c mice sensitized to OVA decreases airway hyperresponsiveness as well as OVA-specific T-helper type 2 (Th2) responses in cervical lymph nodes dramatically.

Conclusion Pam3CSK4 induces Th1/regulatory T cell responses, and as such, is a valid candidate adjuvant for sublingual allergy vaccines.

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