The Role of CD11/CD Integrins In Experimental Asthma

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DESCRIPTION (provided by applicant): Asthma, a common problem that exemplifies a pathologic inflammatory disease process, is characterized by episodic and reversible symptoms of airflow obstruction. The increasing prevalence both in the United States and worldwide reflects a growing public health problem. One recent estimate suggests the total annual cost of asthma to be $5.8 billion, with hospitalization accounting for over half of total expenditures. Traditional therapies of asthma have had limited success in reduction of morbidity and mortality, and it is clear that novel therapies will be needed. Over the last decade it has become widely accepted that asthma is an inflammatory disease and appears to result from activation and proliferation of Th2 lymphocytes. One potential target for therapy of asthma includes the selective inhibition of adhesive proteins responsible for recruitment of Th2 cells into the airway, the absence of which results in abolition of asthma in experimental models. Preliminary data strongly suggest that absence of CD18 results in complete loss of the experimental asthma phenotype in a murine model. CD11/CD18 integrins are heterodimeric, transmembrane proteins consisting of a variable alpha (CDlla, b, c, d) subunit coexpressed with the common beta-2 (CD18) subunit. CD11/CD18 integrins are expressed on a variety of leukocytes and mediate adhesive interactions with endothelium and extracellular matrix in recruiting leukocytes following exposure to any of numerous inflammatory stimuli. The aim of this project is to determine the role of CDll/CD18 integrins in a murine model of allergic airway disease, using mice deficient in CD18, mice singly deficient in each of the four CD11 subunits, and mice with combined deficiencies in multiple CD11 integrins. All genotypes of mice will be immunized with a hybrid antigen of ovalbumin and culture filtrate from Aspergillus fumigatus to induce the experimental asthma phenotype. Parameters to be measured will include airway response to intravenous acetylcholine, bronchoalveolar lavage eosinophilia, ovalbumin- specific IgE production, and goblet cell metaplasia. Enzyme-linked immunospot (ELISPOT) assays will be used to quantitate IL-4 and IFN-gamma producing T cells in spleens and lungs of mutant and wild type mice to assess relative differences in Th2 cell emigration. Adoptive transfer of immunomagnetically purified CD4+ T cells from immunized mutant mice to lymphocyte deficient mice (RAG -/-) and to wild type mice will clarify the effects of specific gene deficiencies on Th2 lymphocyte trafficking to the lung. In vitro T cell stimulation will additionally be performed to determine the capacity for Th2 differentiation in the absence of each of the CD11 integrins.