TH17 Autoimmunity to Type V Collagen in Heart and Lung Transplant

慢性排斥反应是器官移植受者死亡的主要原因。co-PI发现了T辅助细胞17型（TH 17）对V型胶原蛋白α-1链（α-1（V））的反应与慢性排斥反应（肺移植受者中称为闭塞性细支气管炎）之间的新联系，V型胶原蛋白α-1链是正常细胞外基质（ECM）的一种成分。最近的数据显示，冠状动脉粥样硬化性疾病（CAD）和心脏移植物血管病变（CAV）与col（V）自身免疫有类似的联系。我们认为OB期间在肺小气道中观察到的ECM沉积紊乱，以及CAD和CAV的血管是相同的最终共同途径的表现，其中α-1（V）的异常表达和免疫识别起着核心作用。本项目检验了以下假设：由于排斥、缺血再灌注损伤或动脉粥样硬化导致ECM重塑，导致α-1（V）和相关col（V）TH 17特异性CD 4 + T细胞和B细胞反应过度表达，从而导致“促炎”基质。项目1（Greenspan）将试图了解“促炎基质”的结构偏差，在小鼠中使用靶向转基因或敲除方法，导致肺或心脏过度表达α-1（V）或α-2（V）不足。项目2（Burlingham）将研究在MHC II类背景下识别col（V）的CD 4 + T细胞的体内功能。由于胶原结合受体可能影响免疫识别和激活，我们将测试白细胞上的胶原受体LAIR 1和DDR 1在进入正常或紊乱ECM中偏向表位扩散到THI 7途径中的重要性。项目3（Wilkes）将检验以下假设：产生致病性抗col（V）特异性抗体的B细胞在肺移植排斥的发病机制中具有作用，并且它们的合成完全依赖于无序基质中的TH 17和单核细胞/巨噬细胞。这个研究小组已经非常成功地确定了col（V）在OB、CAD和CAV中的中心作用。如果目前的提议成功，研究人员将为该领域开发工具，以推进对一种常见组织抗原的TH 17驱动反应的解剖，这种抗原对肺和心脏移植以及动脉粥样硬化有显著影响。

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.