Severe allergic asthmatic disease is characterized by significant airway structure changes and chronic inflammation predominated by eosinophils that accompany a complex immune response. The most severe airways disease has a continuum that progresses to a steroid resistant state that makes these patients difficult to maintain. In this proposal we have built upon our earlier work on stem cell factor (SCF, kitlg) and taken advantage of its complex biology to develop a targeting strategy to make monoclonal antibodies (Mab) that block the disease associated isoform of SCF to therapeutically attenuate chronic steroid resistant disease including during a viral exacerbation. Eosinophils are known to be involved in chronic severe disease and their activation locally within the airway appear to participate in the development of the remodeling that occurs during this chronic disease. Our lab has previously identified that SCF, through its receptor c-kit, activates eosinophils leading to the production of profibrotic factors. Additionally, fibroblasts from lungs of chronic asthmatic mice have high levels of SCF that promote the activation of eosinophils during cellular interaction. Data provided for this proposal indicate that during chronic allergic responses in the lung that a particular isoform of SCF, SCF248, is expressed that also predominantly is expressed by fibroblasts from allergic mice. The use of antibody that targets SCF248 and not the alternatively spliced version of SCF, SCF220, have clinical therapeutic advantages since this latter isoform (and not SCF248) is imperative for erythropoiesis. In addition, our new preliminary data provided for this revision demonstrate novel findings that SCF248 promotes ILC2 activation and production of Th2 cytokines. Development of a specific Mab with high affinity for SCF248 has allowed generation of preliminary data demonstrating efficacy in a steroid resistant model of allergic asthma as well as the ability to block in vitro assays of SCF248-induced eosinophil and ILC2 activation. Together, these data build the foundation to further extend our knowledge of this complex biology that contributes to the chronicity and severity of allergic airway responses resulting in steroid resistant disease. We will test the hypothesis that expression of the SCF248 isoform during allergic airway responses augments the progression of disease via eosinophil and ILC2 activation that leads to myofibroblast differentiation and peribronchial remodeling promoting severe steroid resistant disease. We have developed a number of important reagents and assays to allow our studies to help define the mechanisms that underlie these responses. In addition to specific Mab development, we will take advantage of a SCFfl/fl mouse genetic model by crossing to a Collagen 1-CRE mouse that will delete SCF primarily in fibroblasts. In addition, our studies will extend into a viral exacerbation model that will provide additional insight into severe exacerbations, which is a common cause of severe asthmatic disease development in humans.
The development of chronic severe asthma continues to be more completely elucidated to further understand the mechanisms that can be targeted for therapeutic intervention. This proposal will explore the role of stem cell factor (SCF) and the ability to attenuate severe steroid resistant disease by blocking SCF with a specific monoclonal antibody developed by our laboratory. Studies will examine the mechanisms involved in eosinophil activation by SCF and their role in this chronic and severe disease.
