Asthma is a common inflammatory disease of the airways. The morbidity and mortality from asthma have continued to increase, despite usage of currently available therapeutic agents. This has prompted an intense search for new methods of treating asthma and allergic inflammation. Evidence indicates that airway eosinophilia, elevated serum IgE, and Th2 cytokine production play important roles in the pathogenesis of allergic airway inflammation and bronchial hyperresponsiveness. Prior studies have reported that IL-12 promotes Th1 cytokines, but inhibits Th2 cytokine synthesis and suppresses IgE production. Based on these properties, it was hypothesized that IL-12 treatment may suppress allergic airway inflammation. A mouse model of allergen-induced eosinophilic lung inflammation was developed to test this hypothesis. Preliminary results indicate that IL-12 treatment of mice inhibits bronchoalveolar lavage (BAL) eosinophilia following intratracheal allergen challenge, decreases allergen-specific serum IgE levels, inhibits tracheal ring reactivity to acetylcholine in vitro, and downregulates expression of IL-4, IL-5 and IL- 10 (Th2 cytokines) mRNA in unfractionated late phase BAL cells. The overall objective of this proposal is to further define the effects of IL- 12 in the same murine model. This will be accomplished by testing the following hypothesis: (l) IL-12 treatment decreases the number of eosinophils and the extent of eosinophil degranulation in the BAL fluids and in the airway mucosa and submucosa. (2) IL-12 treatment decreases tracheal ring reactivity to acetylcholine. (3) IL-12 treatment alters cytokines mRNA expression in BAL T-helper cells, by downregulating Th2 cytokines and upregulating Th1 cytokines. (4) IL-12 treatment decreases the number of CD4+ T-cells producing Th2 cytokines, but increases the number producing Th1 cytokines in the lungs. These studies may set the stage for future clinical research evaluating IL-12 as a therapeutic agent for asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI001539-04
Application #
6168719
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
1997-09-15
Project End
2001-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$116,370
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555