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

Clin Exp Allergy. 2008 Oct;38(10):1668-79. doi: 10.1111/j.1365-2222.2008.03036.x. Epub 2008 Jun 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / deficiency
  • Adaptor Proteins, Vesicular Transport / immunology
  • Adjuvants, Immunologic / administration & dosage*
  • Allergens / immunology
  • Aluminum Hydroxide / administration & dosage*
  • Animals
  • Antibodies / blood
  • Asthma / immunology
  • Asthma / prevention & control*
  • Bronchoalveolar Lavage Fluid / immunology
  • Cells, Cultured
  • Cytokines / analysis
  • Cytokines / immunology
  • Disease Models, Animal
  • Female
  • Interferon-gamma / immunology
  • Interleukin-12 / deficiency
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Lipopolysaccharides / administration & dosage*
  • Lung / immunology
  • Lung / pathology
  • Mice
  • Mice, Inbred BALB C
  • Myeloid Differentiation Factor 88 / immunology
  • Ovalbumin / immunology
  • Phospholipids / pharmacology
  • Toll-Like Receptor 4 / agonists*
  • Toll-Like Receptor 4 / immunology


  • Adaptor Proteins, Vesicular Transport
  • Adjuvants, Immunologic
  • Allergens
  • Antibodies
  • Cytokines
  • ER 803022
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Phospholipids
  • TICAM-1 protein, mouse
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Interleukin-12
  • Aluminum Hydroxide
  • Interferon-gamma
  • Ovalbumin