title: Toll-like receptor-2 agonist-allergen coupling efficiently redirects Th2 cell responses and inhibits allergic airway eosinophilia.
abstract: Toll-like receptor (TLR) agonists beneficially modulate allergic airway inflammation. However, the efficiency of TLR agonists varies considerably, and their exact cellular mechanisms (especially of TLR 2/6 agonists) are incompletely understood. We investigated at a cellular level whether the administration of the pharmacologically improved TLR2/6 agonist S-[2,3-bispalmitoyiloxy-(2R)-propyl]-R-cysteinyl-amido-monomethoxy polyethylene glycol (BPP) conjugated to antigenic peptide (BPP-OVA) could divert an existing Th2 response and influence airway eosinophilia. The effects of BPP-OVA on airway inflammation were assessed in a classic murine sensitization/challenge model and an adoptive transfer model, which involved the adoptive transfer of in vitro differentiated ovalbumin (OVA)-specific Th2 cells. Functional T-cell stimulation by lung dendritic cells (DCs) was determined both in vitro and in vivo, combined with a cytokine secretion analysis. A single mucosal application of BPP-OVA efficiently delivered antigen, led to TLR2-mediated DC activation, and resulted in OVA-specific T-cell proliferation via lung DCs in vivo. In alternative models of allergic airway disease, a single administration of BPP-OVA before OVA challenge (but not BPP alone) significantly reduced airway eosinophilia, most likely through altered antigen-specific T-cell stimulation via DCs. Analyses of adoptively transferred Th2-biased cells after BPP-OVA administration in vivo suggested that BPP-OVA guides antigen-specific Th2 cells to produce significantly higher amounts of IFN-γ upon allergen challenge. In conclusion, our data show for the first time that a single mucosal administration of a TLR 2/6 agonist-allergen conjugate can provoke IFN-γ responses in Th2-biased cells and alleviate allergic airway inflammation.
authors.affiliation: Department for Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany.
authors.forename: Jayendra Kumar
authors.initials: JK
authors.lastname: Krishnaswamy
authors.forename: Adan Chari
authors.initials: AC
authors.lastname: Jirmo
authors.forename: Abdul Mannan
authors.initials: AM
authors.lastname: Baru
authors.forename: Thomas
authors.initials: T
authors.lastname: Ebensen
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzmán
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Georg M N
authors.initials: GM
authors.lastname: Behrens
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D004802:Eosinophilia / Q000276:immunology* / Q000473:pathology; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D012130:Respiratory Hypersensitivity / Q000276:immunology; D012137:Respiratory System / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000819:agonists / Q000378:metabolism
chemical_list: D000485:Allergens; D015848:Interleukin-5; D055666:Lipopeptides; C549816:S-(2,3-bispalmitoyloxypropyl)-cysteinyl-amido-monomethoxyl polyethylene glycol; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D011092:Polyethylene Glycols; D007371:Interferon-gamma; D010047:Ovalbumin