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Airway House Dust Extract Exposures Modify Allergen-Induced Airway Hypersensitivity Responses by TLR4-Dependent and Independent Pathways¹

Diane Lam^*, Nicholas Ng^*, Steve Lee^*, Glenda Batzer^* and Anthony A. Horner^2,*,

^* Department of Medicine and Department of Pediatrics, University of California San Diego, La Jolla, CA 92093

TLR ligands and other allergen-nonspecific immunostimulatory molecules are ubiquitous in ambient air and have profound modulatory activities in animal models of allergic asthma. However, several of these molecules have been shown to promote exaggerated Th2-biased airway hypersensitivity responses (AHRs), whereas others attenuate the asthmatic phenotype. Therefore, it has proven difficult to extrapolate experimental results with purified molecules toward a more general understanding of the allergen-nonspecific immunomodulatory influence of living environments on the natural history of allergic asthma. These investigations determined how regular and intermittent airway exposures to an unpurified, but sterile house dust extract standard (HDEst) affected the OVA-specific AHR and immune status of previously Th2-sensitized mice. Low-dose daily and high-dose intermittent HDEst exposures modulated ongoing AHRs considerably, reducing eosinophil recruitment and methacholine responsiveness, while increasing neutrophilic inflammation. However, only daily airway delivery of low-dose HDEst attenuated OVA-specific Th2 cytokine production and Th2-biased AHRs to allergen challenge 1 mo later. Finally, whereas LPS mimicked many of the immunomodulatory characteristics of HDEst in this murine asthma model, daily airway HDEst delivery was highly effective in attenuating the AHR of OVA/alum-sensitized TLR4-deficient mice. Taken together, these investigations provide direct evidence that living environments contain allergen-nonspecific immunostimulatory molecules that influence the airway hypersensitivity status of allergen-sensitized mice by TLR4-dependent and independent mechanisms.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant AI061772 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Anthony A. Horner, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663. E-mail address: ahorner{at}ucsd.edu

³ Abbreviations used in this paper: ISS-ODN, immunostimulatory sequence oligodeoxynucleotide; AHR, airway hypersensitivity response; BALF, bronchoalveolar lavage fluid; BLN, bronchial lymph node; HDE, house dust extract; HDEst, HDE standard; i.n., intranasal; ko, knockout; Mch, methacholine; WT, wild type.