Author

Stacey Ritz

Date of Award

10-2003

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. Manel Jordana

Abstract

Atopic asthma is immunologically-driven condition characterized by reversible bronchoconstriction and Th2-polarized eosinophilic airways inflammation. As such, the development of Th2 responses is a key step in the pathogenesis of the disease. We utilised a murine model of respiratory mucosal sensitization to examine the roles of different cytokines in the generation of polarized immune-inflammatory responses in the airways. Mice were sensitized to ovalbumin (OVA) by daily aerosol exposure in the context of airway expression of GM-CSF, resulting in a Th2-polarized eosinophilic inflammatory response in the airways, reminiscent of asthma; the addition of IL-12 to the airway microenvironment deviated this response toward the Th1 phenotype. We analyzed expression of key Th1-and Th2-associated genes in the lymph nodes during Th1- and Th2-polarized sensitization, and showed that cytokine expression compartmentalized to the respiratory tract can have a profound impact on the nature of developing immune responses in the draining lymph nodes. Next, we investigated the necessity for IL-4 during GM-CSF-driven respiratory mucosal sensitization. We analyzed a variety of Th2-associated factors, including transcription factors, cytokines, chemokine receptors, and cell surface markers, and found that IL-4 was not necessary for Th2-polarization in this model. Finally, we examined whether IL-10 played a rol in mediating Th2 polarization, and observed that mice treated with anti-IL-10 antibodies or genetically deficient in IL-10 showed impaired development of Th2-polarized immune-inflammatory responses. This research highlights the importance of the cytokine microenvironment of the airways in determining the nature of the ensuing immune-inflammatory response, and defines some of the molecular requirements for the polarization of Th responses during respiratory mucosal sensitization in vivo.


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