Phenotype and function of nasal dendritic cells.

Intranasal (i.n.) vaccination generates immunity across local, regional, and distant sites. However, nasal dendritic cells (DCs), pivotal for the induction of i.n. vaccine-induced immune responses, have not been studied in detail. Here, by using a variety of parameters, we define nasal DCs in mice and humans. Distinct subsets of "classical" DCs, dependent on the transcription factor zbtb46 were identified in the murine nose. The murine nasal DCs were Fms-related tyrosine 3 kinase ligand responsive and displayed unique phenotypic and functional characteristics, including the ability to present antigen, induce an allogeneic T-cell response, and migrate in response to lipopolysaccharide or live bacterial pathogens. Importantly, in a cohort of human volunteers, BDCA-1(+) DCs were observed to be the dominant nasal DC population at steady state. During chronic inflammation, the frequency of both BDCA-1(+) and BDCA-3(hi) DCs was reduced in the nasal tissue, associating the loss of these immune sentinels with chronic nasal inflammation. The present study is the first detailed description of the phenotypic, ontogenetic, and functional properties of nasal DCs, and will inform the design of preventative immunization strategies as well as therapeutic modalities against chronic rhinosinusitis.

Toll-like receptor 4 agonists adsorbed to aluminium hydroxide adjuvant attenuate ovalbumin-specific allergic airway disease: role of MyD88 adaptor molecule and interleukin-12/interferon-gamma axis.

BACKGROUND: Epidemiological and experimental data suggest that bacterial lipopolysaccharides (LPS) can either protect from or exacerbate allergic asthma. Lipopolysaccharides trigger immune responses through toll-like receptor 4 (TLR4) that in turn activates two major signalling pathways via either MyD88 or TRIF adaptor proteins. The LPS is a pro-Type 1 T helper cells (Th1) adjuvant while aluminium hydroxide (alum) is a strong Type 2 T helper cells (Th2) adjuvant, but the effect of the mixing of both adjuvants on the development of lung allergy has not been investigated. OBJECTIVE: We determined whether natural (LPS) or synthetic (ER-803022) TLR4 agonists adsorbed onto alum adjuvant affect allergen sensitization and development of airway allergic disease. To dissect LPS-induced molecular pathways, we used TLR4-, MyD88-, TRIF-, or IL-12/IFN-gamma-deficient mice. METHODS: Mice were sensitized with subcutaneous injections of ovalbumin (OVA) with or without TLR4 agonists co-adsorbed onto alum and challenged with intranasally with OVA. The development of allergic lung disease was evaluated 24 h after last OVA challenge. RESULTS: Sensitization with OVA plus LPS co-adsorbed onto alum impaired in dose-dependent manner OVA-induced Th2-mediated allergic responses such as airway eosinophilia, type-2 cytokines secretion, airway hyper-reactivity, mucus hyper production and serum levels of IgE or IgG1 anaphylactic antibodies. Although the levels of IgG2a, Th1-affiliated isotype increased, investigation into the lung-specific effects revealed that LPS did not induce a Th1 pattern of inflammation. Lipopolysaccharides impaired the development of Th2 immunity, signaling via TLR4 and MyD88 molecules and via the IL-12/IFN-gamma axis, but not through TRIF pathway. Moreover, the synthetic TLR4 agonists that proved to have a less systemic inflammatory response than LPS also protected against allergic asthma development. CONCLUSION: Toll-like receptor 4 agonists co-adsorbed with allergen onto alum down-modulate allergic lung disease and prevent the development of polarized T cell-mediated airway inflammation.