Date of Graduation

8-2012

Document Type

Thesis (MS)

Program Affiliation

Microbiology and Molecular Genetics

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Magnus Hook, Ph.D.

Committee Member

Theresa Koehler, Ph.D.

Committee Member

Jagannadha K. Sastry, Ph.D.

Committee Member

Hung Ton-That, Ph.D.

Abstract

Allergen-induced asthma is the leading form of asthma and a chronic condition worldwide. Common allergens are known to contribute to the pathogenesis of this disease. Murine models of allergic asthma have mostly used an intraperitoneal route of sensitization (not airway) to study this disease. Allergic asthma pathophysiology involves the activation of TH2-specific cells, which triggers production of IgE antibodies, the up-regulation of TH2-specific cytokines (i.e. IL-4, IL-5, IL-9 and IL-13), increased airway eosinophilia, and mucin hypersecretion. Although there are several therapeutics currently treating asthmatic patients, some of these treatments can result in drug tolerance and may be linked to increased mortality. CpG oligodeoxynucleotides (ODNs) is a synthetic ligand that targets Toll-like Receptor (TLR) 9. It has been evaluated as a therapeutic agent for the treatment of cancer, infectious diseases, and for treating allergy and asthma. PUL-042 is also a synthetic TLR ligand and is composed of two agonists against TLR2/6 heterodimer and TLR9. Previous studies have evaluated PUL-042 for its ability to confer resistance against bacterial and viral lung infection. These findings, combined with studies performed using CpG ODNs, led to speculation that PUL-042 dampens the immune response in allergen-induced asthma. My thesis research investigated airway route sensitization and airway delivery of PUL-042 to evaluate its effects in reducing an allergen-induced asthma phenotype in a murine model. The results of this study contribute to the foundation for future investigations to evaluate the efficacy of PUL-042 as a novel therapy in allergic-asthma disease.

Keywords

allergen-induced asthma, ovalbumin (OVA), TH2-specific cells, IgE antibodies, TH2-specific cytokines, airway eosinophilia, CpG oligodeoxynucleotides (ODNs), synthetic ligand, PUL-042 (TLR agonists), TLR2/6 heterodimer and TLR9