Asthma is a chronic disease of the airways characterized by reversible airflow obstruction. Asthma affects nearly 10% of the US population and is increasing in prevalence. The disease is characterized by shortness of breath and wheezing and disproportionately affects children. In fact, asthma is the leading cause of school absenteeism. Additionally, the direct health costs of this disease exceed $50 billion annually and there is no cure. Clearly a better understanding of the disease is required with the goal of more effective therapeutics or even prevention. Toward this goal, we propose to investigate the role of the eosinophil in this disease. The eosinophil is a white blood cell whose numbers correlate with disease severity in allergic asthma patients. Animal models of asthma suggest a key role for this cell in disease pathologies and indeed treatments targeting the eosinophil for removal have been successful in reducing asthma exacerbations in a group of severe asthma patients. Nevertheless, the precise mechanism(s) by which eosinophils contribute to this disease remains elusive. We have developed new technology enabling the targeting of specific eosinophil effector activities which allows us to investigate the importance of eosinophil-derived mediators in mouse models of asthma. One of the most promising eosinophil-derived candidates for modulating disease is TGF-1. This cytokine has been shown to modulate remodeling of the airways including smooth muscle thickening, collagen deposition, and epithelial mesenchymal transition. Additionally, this cytokine is important to T cell polarization and suppression of T cel effector activities. Eosinophils have been identified as a primary source of TGF-1 in the lungs of allergic asthma patients. We hypothesize that eosinophil-derived TGF-1 plays a critical role in airway remodeling. In addition we hypothesize that eosinophil-derived TGF-1 modulates T cell populations and activities in the allergic lung and lung-draining lymph nodes. We will explore these hypotheses using our eosinophil specific Cre recombinase (eoCRE) mouse to delete TGF-1 expression exclusively from eosinophils. We will use these animals in mouse models of asthma and assess disease pathology and T cell subsets/activities. The results of these studies will clarify the role of the eosinophil in asthma and provide a better foundation for pursuing nove asthma therapies.
The degree of airway eosinophilia is associated with the severity of disease in asthma patients. However, the mechanisms by which eosinophils contribute to disease have not been defined. We propose to investigate the specific contribution of eosinophil-derived TGF-?1 to remodeling pathologies and immunomodulation in mouse models of asthma. We expect the results of this study will help clarify the role of the eosinophil in allergic asthma and contribute to the development of new therapies for asthma patients.
| Jacobsen, E A; Doyle, A D; Colbert, D C et al. (2015) Differential activation of airway eosinophils induces IL-13-mediated allergic Th2 pulmonary responses in mice. Allergy 70:1148-59 |
