Type V Collagen Prevents Lung Allograft Rejection

V 型胶原蛋白可防止肺同种异体移植排斥

• 批准号: 7479850
• 负责人: David S Wilkes
• 金额: $ 36.75万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7479850
• 关键词: Activated Lymphocyte; Acute; Adhesions; Adoptive Transfer; Alloantigen; Allogenic; Allografting; Antibodies; Antigen-Presenting Cells; Antigens; Area; Atypical lymphocyte; Autoimmune Diseases; Autoimmunity; Autologous; Blocking Antibodies; Blood; Bone Marrow Transplantation; Bronchiolitis; Bronchus-Associated Lymphoid Tissue; CD4 Positive T Lymphocytes; Cause of Death; Cell Adhesion Molecules; Cell physiology; Cells; Cellular Immunity; Chronic; Clinical Treatment; Collagen Type V; Dendritic Cells; Development; Disease; Emigrations; Endothelium; Epithelium; Failure; Gene Silencing; Graft Rejection; Helper-Inducer T-Lymphocyte; Humoral Immunities; Immigration; Immune Sera; Immune response; Immunity; Immunobiology; Immunology; Inflammation; Injury; Interleukin-17; Isogenic transplantation; Laboratories; Leukocytes; Life; Lung; Lung Transplantation; Lung diseases; Lymph Node Tissue; Lymphocyte; Major Histocompatibility Complex; Mediastinal; Mediastinal lymph node group; Mediating; Mesenchymal; Modeling; Organ; Pathogenesis; Pathology; Pathway interactions; Process; Proteins; Rattus; Reporting; Research Personnel; Risk Factors; Role; Site; Somatic Cell; Sphingosine-1-Phosphate Receptor; Staging; Stimulus; Stream; T-Lymphocyte; Testing; Transcript; Transplant Recipients; Transplantation; base; cell motility; cell type; clinically relevant; cytokine; isoimmunity; lung allograft; lymph nodes; migration; novel; prevent; programs; receptor; response

DESCRIPTION (provided by applicant): Lung transplantation is the only definitive therapy for many forms of end stage lung disease. However, survival of the transplant recipient is limited by chronic rejection, known as obliterative bronchiolitis (OB). Rejection episodes are initiated by recipient T cells recognizing donor major histocompatibility complexes (MHC). However, we have reported the rejection response also involves specific immunity to a native protein, type V collagen [col(V)], and that immunity to col(V) is a major risk factor for the development of OB. Therefore, lung transplant rejection is a disease if both allo- and autoimmunity. Immune responses require lymphocyte migration from the blood stream to lymph nodes followed by emigration of activated lymphocytes to sites of inflammation/injury. However, the mechanism of anti-col(V) lymphocyte migration and emigration into and from mediastinal lymph nodes and BALT, respectively, are unknown. In addition, recent studies implicate a novel group of T cells (Th-17) able to induce autoimmune disease in many organs, including the lung. However, the role of Th-17 cells in the pathogenesis of autoimmunity that occurs during lung transplant rejection has not been characterized. Recognition of donor alloantigens occurs via two pathways, direct and indirect; and the two types of rejection, acute and chronic, have been attributed to the activity each pathway, respectively. The current paradigm of direct and indirect allorecognition is based on the ability of donor antigen presenting cells (known as passenger leukocytes) and recipient-derived antigen presenting cells (APCs), respectively, to activate recipient T cells. However, the role of passenger leukocytes and somatic cells in lung grafts to mediate acute rejection and OB is unknown. Furthermore, the requirement for these cells to induce Tregs specific for donor antigens and col(V) has not been reported. Utilizing a rat model of lung transplantation, the current proposal tests the hypothesis that alloimmune-induced autoimmunity to col(V) mediates lung transplant destruction by examining the following specific aims: Aim 1. To determine if the adhesion pathways utilized by col(V)-reactive lymphocytes for migration/emigration to mediastinal nodes and BALT are differentially regulated. Aim 2. To determine the contribution of humoral and Th-17 cellular immunity to the pathogenesis of anti-col(V)-mediated pathology. Aim 3. To determine the contribution of somatic cells and passenger leukocytes in the transplanted lung in development of Tregs and autoimmunity to col(V) during allograft rejection. This application will investigate the causes of lung transplant rejection which is the leading cause of death in lung transplant recipients. This application may also identify new areas that may allow for new treatments of this clinical problem.

描述（由申请人提供）：肺移植是许多形式的末期肺部疾病的唯一明确治疗。然而，移植受者的存活受到慢性排斥的限制，称为闭塞性支气管炎（OB）。排斥发作是由识别供体主要组织相容性复合物（MHC）的受体T细胞引发的。但是，我们报告的排斥反应还涉及对天然蛋白的特定免疫力，即V型胶原蛋白[Col（V）]，对Col（V）的免疫力是OB发展的主要危险因素。因此，如果同种和自身免疫，则肺移植排斥是一种疾病。免疫反应需要淋巴细胞从血流迁移到淋巴结，然后将活化的淋巴细胞迁移到炎症/损伤部位。然而，抗癌（V）淋巴细胞迁移和迁移到纵隔淋巴结和BALT的机制尚不清楚。此外，最近的研究暗示了一组新型的T细胞（TH-17）能够在包括肺在内的许多器官中诱导自身免疫性疾病。但是，尚未表征Th-17细胞在肺移植排斥期间发生的自身免疫发病机理中的作用。识别供体同种剂通过两种直接和间接的途径发生。急性和慢性排斥的两种类型分别归因于每个途径的活动。当前的直接和间接同种识别的范式基于供体抗原呈递细胞（称为乘客白细胞）和受体衍生的抗原呈递细胞（APC）的能力，激活受体T细胞。然而，乘客白细胞和体细胞在肺移植物中介导急性排斥和OB的作用尚不清楚。此外，尚未报道这些细胞诱导针对供体抗原和Col（V）的Treg的要求。 Utilizing a rat model of lung transplantation, the current proposal tests the hypothesis that alloimmune-induced autoimmunity to col(V) mediates lung transplant destruction by examining the following specific aims: Aim 1. To determine if the adhesion pathways utilized by col(V)-reactive lymphocytes for migration/emigration to mediastinal nodes and BALT are differentially受监管。目的2。确定体液和TH-17细胞免疫对抗Col（V）介导病理学的发病机理的贡献。目标3。确定在同种异体移植排斥期间，在移植肺中的体细胞和乘客白细胞在发育中的肺和自身免疫性对Col（V）的贡献。该应用将调查肺移植排斥反应的原因，这是肺移植受者死亡的主要原因。该应用程序还可以确定可能允许对该临床问题进行新的治疗方法的新领域。