Fibrotic lung diseases are increasingly important lung conditions, with a rising incidence in the general population. Our application focuses on bronchiolitis obliterans syndrome (BOS), a fibrotic disease that occurs after human lung transplantation and is the primary reason for poor long-term survival among lung transplant recipients. Compelling evidence suggests that immune dysregulation involving regulatory T cells (Tregs), effector/memory T cells, and autoimmunity to type V collagen (Col-V) occurs in BOS. Normally hidden from the immune system, Col-V may be exposed in the setting of lung injury or inflammation and become an immune system target. Because ofthe importance of immune dysregulation and autoimmunity in the pathogenesis of BOS, the primary hypothesis to be tested is that alterations in Treg or T effector/memory populations and/or their polyfunctional cytokine response to Col-V predict the development of BOS. We will leverage the large clinical transplant population at Duke, prospectively obtained and previously banked PB samples, and the expertise of a highly experienced multi-disciplinary team of investigators. We will test this hypothesis through complementary aims that use polychromatic flow cytometry to measure T subsets in the peripheral blood (Aim 1) and their Col-V antigen specific responses (Aim 2) and apply innovative statistics and bioinformatics to identify precise cellular predictors of BOS (Aim 3). Our bioinformatics approach is designed to identify novel candidate immune biomarkers using multivariate mixture modeling and to facilitate application into clinical diagnostics using discriminative information measures that define the minimal group of markers necessary to identify predictive cellular subsets. In CADET-2, we will use these approaches to identify individual at high risk for BOS and test the idea that specific clinical interventions, such as intensification of immunosuppression, will delay or prevent its onset. As immune dysregulation appears a central theme across many chronic fibrotic lung diseases, a long-term development goal is to use the clinical, technical and bioinformatics expertise established through these proof-of-concept studies in lung transplant to bring advanced immune profiling to the forefront of clinical diagnostics in pulmonary medicine.
Although lung transplantation benefits many patients with advanced lung disease, long-term outcomes after lung transplantation are limited by progressive ainway fibrosis called bronchiolitis obliterans. Our research will identify novel immune biomarkers in the blood that can identify patients at high risk for this condition, thereby allowing for early and more effective interventions that will improve long-term transplant outcomes
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