title: Toll-like receptor 2 agonist Pam3CSK4 enhances the induction of antigen-specific tolerance via the sublingual route.
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.
  
  
  CONCLUSIONS
  Pam3CSK4 induces Th1/regulatory T cell responses, and as such, is a valid candidate adjuvant for sublingual allergy vaccines.
authors.affiliation: Research and Development, Stallergènes SA, Antony, Cedex, France.
authors.forename: V
authors.initials: V
authors.lastname: Lombardi
authors.forename: L
authors.initials: L
authors.lastname: Van Overtvelt
authors.forename: S
authors.initials: S
authors.lastname: Horiot
authors.forename: H
authors.initials: H
authors.lastname: Moussu
authors.forename: H
authors.initials: H
authors.lastname: Chabre
authors.forename: A
authors.initials: A
authors.lastname: Louise
authors.forename: A-M
authors.initials: AM
authors.lastname: Balazuc
authors.forename: L
authors.initials: L
authors.lastname: Mascarell
authors.forename: P
authors.initials: P
authors.lastname: Moingeon
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000286:Administration, Sublingual; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001249:Asthma / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003888:Desensitization, Immunologic / Q000379:methods*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D055666:Lipopeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D016966:Porphyromonas gingivalis / Q000737:chemistry; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D013682:Teichoic Acids / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000819:agonists*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D055666:Lipopeptides; D008070:Lipopolysaccharides; C508075:Pam(3)CSK(4) peptide; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D016753:Interleukin-10; C009900:lipoteichoic acid; D007371:Interferon-gamma; D010047:Ovalbumin