Am. J. Respir. Crit. Care Med., Volume 156, Number 4, October 1997, S89-S96

The Genetics of Allergen-Induced Airway Hyperresponsiveness in Mice

MARSHA WILLS-KARP and SUSAN L. EWART

Department of Environmental Health Sciences, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland; and Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan

Airway hyperresponsiveness (AHR) is a fundamental aspect of asthma that has been shown to be influenced by both environmental and genetic factors. Antigen sensitization and challenge of the A/J inbred mouse strain induced AHR, eosinophilic airway inflammation, and lung goblet cell hyperplasia. We discuss the evidence that supports the role of T helper cells and their subsets in determining the airway inflammatory and contractile responses to antigen in a mouse model. Airway hyperresponsiveness and pulmonary eosinophilic inflammation induced by antigen challenge are associated with a Th2 pattern of cytokine expression in the murine lung. CD4+ T cells mediate the airway reaction to antigen, as depletion of CD4+ T cells attenuates the response. The presence of interleukin (IL)-4 induces the Th2 type of immune response, and this cytokine is required for mice to manifest AHR and inflammation to antigen. The Th1 type of immune response is stimulated by IL-12. Antigen-mediated AHR and inflammation are inhibited by IL-12 administration. Airway hyperresponsiveness in the noninflammatory state (without antigen treatment) is inherited in A/J and C3H/HeJ inbred mouse strains. One quantitative trait locus for AHR in progeny derived from these strains is located on murine chromosome 6. We propose that antigen-inducd AHR and inflammation also have heritable components. Based on the available immunological data, genes that influence the balance between Th1 and Th2 cells are logical candidate genes for antigen-induced AHR and inflammation. Knowledge of the genes that determine this phenotype will help us understand the mechanisms of human asthma. Wills-Karp M, Ewart SL. The genetics of allergen-induced airway hyperresponsiveness in mice.

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