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。研究人员发现，肺移植受者的慢性排斥反应称为闭塞性毛细支气管炎，与正常细胞外基质(ECM)的一种成分--V型胶原α-1链的辅助性T细胞17型(TH17)反应之间存在新的联系。最近的数据显示，COL(V)自身免疫与冠状动脉粥样硬化性疾病(CAD)和心脏移植物血管病变(CAV)有类似的联系。我们认为OB时肺小路ECM沉积紊乱，CAD和CAV的血管是同一最终共同通路的表现，而α-1(V)的异常表达和免疫识别在其中起核心作用。该计划项目测试了一种假设，即排斥、缺血再灌注损伤或动脉粥样硬化导致的ECM重建会由于α-1(V)和相关的COL(V)TH17特异性的CD4+T细胞和B细胞反应的过度表达而导致“促炎”基质的形成。项目1(格林斯潘)将在小鼠身上使用有针对性的转基因或基因敲除方法，试图了解“促炎基质”的结构偏差，导致肺或心脏过度表达α-1(V)或缺乏α-2(V)。项目2(Burlingham)将在MHC II类的背景下检测识别COOL(V)的CD4+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，我们将测试进入正常或紊乱的ECM的白细胞上胶原受体LAIR1和DDR1在偏向表位扩散到THI7途径中的重要性。项目3(Wilkes)将测试一种假设，即产生致病性抗Colo(V)特异性抗体的B细胞在肺移植排斥反应的发病机制中发挥作用，并且它们的合成完全依赖于TH17和无序基质中的单核/巨噬细胞。这个研究团队已经非常成功地确定了COL(V)在OB、CAD和CAV中的核心作用。如果目前的提议成功，研究人员将为该领域开发工具，以深入剖析TH17驱动的对一种常见组织抗原的反应，该抗原显著影响肺和心脏移植，以及动脉粥样硬化。

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.