1. Toll-like receptor 2 agonist Pam3CSK4 enhances the induction of antigen-specific tolerance via the sublingual route.
- Author
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Lombardi V, Van Overtvelt L, Horiot S, Moussu H, Chabre H, Louise A, Balazuc AM, Mascarell L, and Moingeon P
- Subjects
- Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic pharmacology, Administration, Sublingual, Animals, Antigen Presentation immunology, Asthma immunology, Asthma physiopathology, Bronchial Hyperreactivity immunology, Bronchial Hyperreactivity therapy, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Cytokines genetics, Cytokines metabolism, Dendritic Cells drug effects, Dendritic Cells immunology, Dendritic Cells metabolism, Gene Expression drug effects, Humans, Interferon-gamma metabolism, Interleukin-10 metabolism, Lipopeptides administration & dosage, Lipopeptides pharmacology, Lipopolysaccharides pharmacology, Lymph Nodes immunology, Lymph Nodes metabolism, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Ovalbumin immunology, Porphyromonas gingivalis chemistry, T-Lymphocytes, Helper-Inducer immunology, Teichoic Acids pharmacology, Adjuvants, Immunologic therapeutic use, Asthma therapy, Desensitization, Immunologic methods, Lipopeptides therapeutic use, Toll-Like Receptor 2 agonists
- Abstract
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-gamma 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.
- Published
- 2008
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