TH17 Autoimmunity to Type V Collagen in Heart and Lung Transplant

TH17 在心肺移植中对 V 型胶原的自身免疫

• 批准号: 7765108
• 负责人: David S Wilkes
• 金额: $ 160.71万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7765108
• 关键词: TH17; Autoimmunity; Type; Collagen; Heart

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.

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，辅助t - 17型（TH17）对V型胶原α -1链（正常细胞外基质（ECM）的一种成分）的反应与肺移植受者慢性排斥反应（即闭塞性细支气管炎）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疾病（CAD）和心脏异体移植血管病变（CAV）之间存在类似的联系。我们认为，OB期间肺小气道中的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发挥了核心作用。该项目验证了由排斥反应、缺血再灌注损伤或动脉粥样硬化引起的ECM重塑由于α -1 (V)和相关的col(V) th17特异性CD4+ T细胞和B细胞反应的过度表达而导致“促炎”基质的假设。项目1 （Greenspan）将寻求理解“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)缺乏。项目2 （Burlingham）将研究在MHC II类背景下识别col(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，我们将测试胶原受体LAIR1和DDR1在白细胞进入正常或紊乱的ECM中偏向表位扩散到THI7途径中的重要性。Project 3 （Wilkes）将验证产生致病性抗col(V)特异性抗体的B细胞在肺移植排斥的发病机制中发挥作用的假设，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。这组研究人员已经非常成功地确定了col(V)在OB、CAD和CAV中的核心作用。如果目前的提议获得成功，研究人员将开发出工具，推动该领域深入研究TH17驱动的对一种常见组织抗原的反应，这种抗原对肺和心脏移植以及动脉粥样硬化有显著影响。