title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: Bortolatto
authors.forename: E
authors.initials: E
authors.lastname: Borducchi
authors.forename: D
authors.initials: D
authors.lastname: Rodriguez
authors.forename: A C
authors.initials: AC
authors.lastname: Keller
authors.forename: E
authors.initials: E
authors.lastname: Faquim-Mauro
authors.forename: K R
authors.initials: KR
authors.lastname: Bortoluci
authors.forename: D
authors.initials: D
authors.lastname: Mucida
authors.forename: E
authors.initials: E
authors.lastname: Gomes
authors.forename: A
authors.initials: A
authors.lastname: Christ
authors.forename: S
authors.initials: S
authors.lastname: Schnyder-Candrian
authors.forename: B
authors.initials: B
authors.lastname: Schnyder
authors.forename: B
authors.initials: B
authors.lastname: Ryffel
authors.forename: M
authors.initials: M
authors.lastname: Russo
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000485:Allergens / Q000276:immunology; D000536:Aluminum Hydroxide / Q000008:administration & dosage*; D000818:Animals; D000906:Antibodies / Q000097:blood; D001249:Asthma / Q000276:immunology / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D010743:Phospholipids / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000276:Adjuvants, Immunologic; D000485:Allergens; D000536:Aluminum Hydroxide; D000906:Antibodies; D016207:Cytokines; D007371:Interferon-gamma; D018664:Interleukin-12; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D010047:Ovalbumin; D010743:Phospholipids; D051197:Toll-Like Receptor 4; C475978:ER 803022; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C495345:TLR4 protein, human