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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

基本信息

批准号：
8713903
负责人：
David S Wilkes
金额：
$ 157.11万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/8713903
关键词：
Accounting Acids Acute Address Affinity Allogenic Alveolar Animals Antibodies Anticol Antigen-Presenting Cells Antigens Apical Arterial Fatty Streak Atherosclerosis Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Automobile Driving B-Lymphocytes Binding Biochemistry Blood Vessels Bronchiolitis Bronchiolitis Obliterans CD4 Positive T Lymphocytes Cause of Death Cell physiology Cells Cellular Immunity Chronic Clinical Collaborations Collagen Collagen Receptors Collagen Type I Collagen Type II Collagen Type V Complex Connective Tissue Coronary Coronary Vessels Cytoskeleton DDR1 gene DDR2 gene Data Dendritic Cells Deposition Development Disease Down-Regulation Employee Strikes Environment Epithelial Cells Epithelium Epitopes Equilibrium Event Exposure to Extracellular Matrix Fibrillar Collagen Goals Graft Rejection HLA-DR Antigens Heart Heart Diseases Heart Transplantation Helper-Inducer T-Lymphocyte Human Humoral Immunities Immune Immune response Immune system Immunity Immunoglobulins Immunology Inflammation Inflammatory Injury Integral Membrane Protein Interleukin-17 Interleukin-4 Interleukin-6 Ischemia Isogenic transplantation Knock-out Lead Learning Lesion Leukocytes Life Ligands Link Lung Lung Transplantation Lung diseases MHC Class II Genes Macrophage Activation Mediating Mediator of activation protein Mesenchymal Metalloproteases Methods Minor Modeling Molecular Biology Mononuclear Mus Normal tissue morphology Organ Organ Transplantation Pathogenesis Pathologic Pathology Pathway interactions Patients Peptide Hydrolases Play Process Production Proliferating Property Rattus Regulatory T-Lymphocyte Reperfusion Injury Reperfusion Therapy Reporting Research Research Personnel Risk Factors Role Science Signal Transduction Smooth Muscle Myocytes Solid Source Staging Staining method Stains Surface Syndrome T cell response T-Lymphocyte TGFB1 gene TNF gene Techniques Testing Tetanus Therapeutic Intervention Tissue Sample Tissues Transgenic Organisms Transplant Recipients Transplantation Vascular Diseases Virus Weight allograft rejection base chemokine cytokine discoidin receptor heart allograft immunogenic in vivo interdisciplinary approach interstitial isoimmunity lung allograft macrophage microbial monocyte novel novel strategies overexpression pathogen programs receptor receptor binding receptor expression research study response tool translational approach transplantation medicine vascular bed

项目摘要

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。联合 PI 发现了 17 型 T 辅助细胞 (TH17) 对 V 型胶原蛋白 α-1 链 [α-1 (V)]（正常细胞外基质 (ECM) 的一个组成部分）的反应与肺移植受者慢性排斥反应（称为闭塞性细支气管炎）之间的新联系。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) 和心脏同种异体移植血管病 (CAV) 之间存在类似的联系。我们认为，OB 期间肺小气道中出现的紊乱的 ECM 沉积以及 CAD 和 CAV 的血管是同一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着核心作用。该项目测试了以下假设：排斥、缺血再灌注损伤或动脉粥样硬化导致的 ECM 重塑会由于 alpha-1 (V) 过度表达和相关 col(V) TH17 特异性 CD4+ T 细胞和 B 细胞反应而产生“促炎”基质。项目 1（格林斯潘）将寻求了解“促炎基质”的结构偏差，在小鼠中使用靶向转基因或基因敲除方法，导致肺或心脏过度表达 alpha-1 (V) 或缺乏 alpha-2(V)。项目 2（Burlingham）将检查在 MHC II 类背景下识别 col(V) 的 CD4+ T 细胞的体内功能。由于胶原蛋白结合受体可能会影响免疫识别和激活，因此我们将测试胶原蛋白受体 LAIR1 和 DDR1 对进入正常或紊乱 ECM 的白细胞在偏向表位扩散到 THI7 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 细胞在肺移植排斥反应的发病机制中发挥作用，并且它们的合成完全取决于无序基质内的 TH17 和单核细胞/巨噬细胞。该研究团队非常成功地确定了 col(V) 在 OB、CAD 和 CAV 中的核心作用。如果当前的提议成功，研究人员将为该领域开发工具，以推进剖析 TH17 驱动的对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着影响。