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(Chest. 2002;121:13S.)
© 2002 American College of Chest Physicians

Genetic Analysis of Antigen-Induced Airway Manifestations of Asthma Using Recombinant Congenic Mouse Strains*

Antoon J.M. Van Oosterhout, PhD; Prescilla V. Jeurink; Peter C. Groot, PhD; Gerard A. Hofman; Frans P. Nijkamp, PhD and Peter Demant, PhD

* From the Department of Pharmacology and Pathophysiology (Drs. Van Oosterhout, Groot, and Nijkamp, Ms. Jeurink, and Mr. Hofman), Faculty of Pharmacy, Utrecht University, Utrecht, Netherlands; Division of Molecular Genetics (Dr. Demant), Netherlands Cancer Institute, Amsterdam, Netherlands.

Correspondence to: Antoon J.M. Van Oosterhout, PhD, Department of Pharmacology and Pathophysiology, Faculty of Pharmacy, Utrecht University, PO box 80.082, 3508TB Utrecht, Netherlands; e-mail: a.j.m.vanoosterhout{at}pharm.uu.nl

Allergic asthma is a heterogeneous and genetically complex disease that is characterized by the presence of allergen-specific IgE, eosinophilic airway inflammation, and hyperresponsiveness to bronchospasmogenic stimuli. To facilitate the mapping of genes controlling complex asthma traits, we have used a powerful tool, the recombinant congenic strains of mice, which transforms a multigenic difference into a set of monogenic or oligogenic differences.1 This approach offers a higher resolution power than do the standard mouse crosses in mapping segregating quantitative trait loci and in the detection of their potential interactions. In the present study, we compared 4 strains (Ccs/DEM-5, Ccs/DEM-11, Ccs/DEM-12, and Ccs/DEM-18) from a series of 20 strains, each of which carries a random set of 12.5% of genes from the T-helper cell type 1 responder strain STS and 87.5% of genes from the T-helper cell type 2 responder strain BALB/c. Mice were sensitized with ovalbumin (OVA), and later on were repeatedly challenged by the inhalation of an OVA aerosol. Before and after the OVA challenges, serum samples were obtained and the airway responsiveness to nebulized methacholine (dose range, 1.5 to 50 mg/mL) was determined. Finally, BAL was performed, and the number of leukocytes were determined (Table 1 ).


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  		Table 1.. Lung Function and Inflammation*

 
All mouse strains showed increased serum levels of OVA-specific IgE as a result of the OVA inhalation challenge (data not shown). It appears that there is no correlation between the number of BAL eosinophils and the extent of airway hyperresponsiveness. Strain 12 displayed airway eosinophilia but a resistance to hyperresponsiveness. However, the baseline airway responsiveness of strain 12 was higher than that of the other strains. In strain 11, airway hyperresponsiveness was determined predominantly by an increased sensitivity (ie, the dose of methacholine needed to increase baseline values of enhanced pause by 300%) to methacholine, whereas in strains 5 and 18 only a significant increase in the maximal response could be observed. These data demonstrate that different asthma traits like the presence of IgE, eosinophilia, and hyperresponsiveness may be genetically dissociated. Further mapping studies will be carried out to localize the modifier genes involved in specific traits.


   Footnotes
 
Abbreviation: OVA = ovalbumin

This research was supported by a research grant (AF99.23) of the Dutch Asthma Foundation.


   References
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 References
 

  1. Groot, PC, Moen, CJ, Dietrich, W, et al (1992) The recombinant congenic strains for analysis of multigenic traits: genetic composition. FASEB J 6,2826-2835[Abstract]



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