STAT6-Dependent Bridging of Innate and Th2 Adaptive Immunity in the Lung
Abstract
Background: Both the frequency and severity of asthma and allergies have been increasing steadily over the last 2-3 decades. There are at least 300 million asthma sufferers worldwide, and this condition ranks 25th in overall impact on human health (disability and death). Asthma is one of the most expensive of all chronic diseases due to the high cost of repeated healthcare utilization. Concern about high costs and lifelong effects has been rising recently among military personnel, Veterans, and their healthcare providers, in the face of a growing body of evidence linking military deployment with development and/or worsening of asthma and related respiratory symptoms. Recognizing the high impact of these health risks, the Department of Defense (DoD) and Veterans Affairs (VA) have identified the focus of the current proposal (i.e., research related to treatment and prevention of respiratory symptoms and ailments possibly associated with deployed and redeployed military personnel) as a priority research area. The overall objective of this proposal is to characterize the actions of a novel compound developed in our labs (called STAT6-IP), a small protein- or peptide-based inhibitor that reduces both abnormal inflammation in the lungs that can contribute to the development and persistence of asthma. This program of research will benefit from the complementary skills of the applicants: Dr. Elizabeth Fixman, who originally developed the STAT6-IP, has expertise in animal models of asthma and Dr. Brian Ward brings expertise in infectious disease models and inflammation. Prior Work Performed by Applicants: The disease burden caused by asthma has increased dramatically in recent years despite improved understanding of the disease. There is now abundant evidence that asthma is initiated and exacerbated by inflammatory cells called Th2 cells. STAT-6 is a protein that works inside cells to promote the development of Th2 cells as well as airway inflammation and "irritability" in animal models of asthma. We are investigating a novel therapeutic molecule that we developed specifically to inhibit STAT-6. We have shown that intranasal delivery of this inhibitor reduces asthmatic inflammatory responses in mice with experimentally induced asthma. We have also shown that this inhibitor blocks specific molecules that initiate the abnormal immune response in the lungs. One of these molecules has also been implicated in the perpetuation of asthmatic responses. More recently, we have shown that our inhibitor reduces the development of abnormal inflammation in mice infected with respiratory syncytial virus (RSV). In humans, early-life RSV infection is an important risk factor for the subsequent development and persistence of asthma. Thus, our major goal is to fully define how our STAT6 inhibitor reduces pathology in both asthma and RSV infection. While STAT6-IP delivery via the nose has obvious therapeutic potential for the treatment/prevention of respiratory allergies/asthma, we have not yet looked for possible undesirable effects of our peptide on Th2 responses that are protective against parasite (worm) infections and some other respiratory viruses. Significance: As a potent inhibitor of abnormal Th2-biased airway inflammatory responses, our STAT6 inhibitor may be a promising new therapeutic approach for the treatment and prevention of asthma in humans. Defining how this novel inhibitor works and how specific it is will provide valuable information supporting its further development. The information we obtain will almost certainly be relevant to several other priority research areas of the DoD and VA including lung infections, chronic respiratory conditions, and vaccination programs that target respiratory diseases. Although not specifically the focus of the current proposal, such "lateral" applications of our anticipated results may be highly significant. A full understanding of how STAT6-IP acts to prevent or modify ast
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510698
Entities
People
- Brian J. Ward
Organizations
- McGill University Health Centre
- United States Army