Chronic rejection is the leading cause of death in organ transplant recipients. The co-PIs have discovered a novel link between T-helper type 17 (TH17) responses to the alpha-1 chain of type V collagen [alpha-1 (V)], a component of normal extracellular matrix (ECM) and the process of chronic rejection, known as obliterative bronchiolitis in lung transplants recipients. Recent data show a similar link of col(V) autoimmunity to coronary atherosclerotic disease (CAD) and cardiac allograft vasculopathy (CAV). We propose that disordered ECM deposition seen in small airways of lung during OB, and the vessels of CAD and CAV are manifestations of the same final common pathway in which abnormal expression and immune recognition of alpha-1 (V) play a central role. This program project tests the hypothesis that ECM remodeling resulting from rejection, ischemia reperfusion injury or atherosclerosis results in a "pro-inflammatory" matrix due to overexpression of alpha-1 (V) and associated col(V) TH17-specific CD4+ T cell and B cell responses. Project 1 (Greenspan) will seek to understand the structural bias of a "pro-inflammatory matrix", using targeted transgenic or knockout approaches in mice, resulting in lungs or hearts either overexpressing alpha-1 (V) or deficient in alpha-2(V). Project 2 (Burlingham) will examine the in vivo functions of CD4+ T cells that recognize col(V) in the context of MHC class II. Since collagen binding receptors may impact immune recognition and activation, we will test the importance of collagen receptors, LAIR1 and DDR1, on leukocytes entering a normal or disorded ECM in biasing epitope spreading into a THI7 pathway. Project 3 (Wilkes) will test the hypothesis that B cells producing pathogenic anti-col(V)-specific antibodies have a role in the pathogeneis of lung transplant rejection, and that their synthesis is entirely depend on TH17 and monocytes/macrophages within a disordered matrix. This team of investigators has been highly successful in identifying the central role of col(V) in OB, CAD, and CAV. If the current proposal succeeds, the investigators will have developed tools for the field to advance in dissecting TH17 driven responses to a common tissue antigen that impacts significantly lung and heart transplants, as well as atherosclerosis.
The Studies in this application are directly relevant to the identification of targets for therapeutic intervention to prolong the life of lung and heart transplant recipients as well as those suffering from atherosclerotic heart disease.
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