Although they represent only a small fraction of asthma sufferers, patients with severe refractory asthma (SRA) account for nearly half of healthcare costs relating to asthma treatment. SRA appears to be a heterogeneous set of diseases with different subtypes, characterized by differential levels of granulocyte involvement. These different subtypes may account for why a significant subgroup of SRA patients does not respond to inhaled corticosteroid therapy (ICS). The potential for positive response appears to increase with eosinophil involvement;therefore, identification of the type of granulocyte involvement, neutrophil and/or eosinophil, can be an important diagnostic aid. Currently, granulocyte identification is performed by measures of average eosinophil content, including induced sputum or lavage analysis. Both techniques provide only an estimate of the average cell burden in the lungs and cannot give specific information about cell densities or localization. Our lab has extensive experience in the development of molecular probes for in vivo imaging, and in this work, we propose to develop probes specific for eosinophils to allow three-dimensional, in vivo visualization of eosinophils in inflammatory asthma. We will develop probes detectable by the highly sensitive imaging technique of Positron Emission Tomography (PET) and apply these to an animal model of inflammatory asthma (ovalbumin mouse) known to possess to a robust eosinophil response. Probes will be developed that are targeted to Siglec-8 a surface marker on eosinophils. Probes will be assessed in solution and cell culture models, then applied to image eosinophils in the ovalbumin animal model of asthma. We partner with a co-investigator experienced in the production of these mice who will perform histology to confirm that the imaging results match the actual pattern of eosinophil localization in the animal. The visualization of cell distribution and density in vivo will give us a more detailed understanding o where these cells reside compared to simple sputum cell counts;and identifying where active cells persist in SRA, both in the lung and systemically could lead to a better understanding of why some patients are refractory to treatment. Cell-based imaging has the potential to replace more invasive biopsies in the future. In addition, eosinophils have garnered interest as a potential target for therapeutic intervention. The ability to image the cells in vivo can aid in design of therapy as well as in monitoring the effectiveness of therapy.
We propose to develop imaging methods with the goal of allowing clinicians to identify specific cell types involved in asthma that may indicate whether the asthma will be treatable. Being able to see where and how many of these cells are present in the body can help clinicians understand why some forms of asthma are resistant to treatment, and help us to develop new more effective therapies.
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| Linderholm, Angela L; Bratt, Jennifer M; Schuster, Gertrud U et al. (2014) Novel therapeutic strategies for adult obese asthmatics. Immunol Allergy Clin North Am 34:809-23 |
