Effects of lymphangiogenesis stimulation on lung allograft rejection

刺激淋巴管生成对肺同种异体移植排斥反应的影响

• 批准号: 8570801
• 负责人: Souheil El-Chemaly
• 金额: $ 22.82万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8570801
• 关键词: Acute; Address; Allogenic; Allografting; Antigen Presentation; Biological Markers; Cells; Chronic; Chronic Obstructive Airway Disease; Data; Deposition; Development; Exhibits; Extracellular Matrix; Feedback; Functional disorder; Glycosaminoglycans; Goals; Graft Rejection; Growth Factor; Hamman-Rich syndrome; Histology; Human; Hyaluronan; Image; Implant; Inflammatory; Injury; Interruption; Knowledge; Lead; Liver; Lung; Lung Lavage Fluid; Lung Transplantation; Lung diseases; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic vessel; Monitor; Mus; Mutate; Physiological; Physiology; Play; Process; Proteins; Quality of life; RNA; Research; Resolution; Respiratory physiology; Risk Factors; Role; Staging; Structure of parenchyma of lung; System; Testing; Time; Transplant Recipients; Transplantation; Vascular Endothelial Growth Factor C; Work; Xenograft procedure; allograft rejection; angiogenesis; base; density; effective therapy; graft function; implantation; improved; in vivo; insight; lung allograft; lung imaging; lung injury; lung repair; lymph nodes; lymphatic circulation; migration; mouse model; novel strategies; novel therapeutics; public health relevance; response; success; therapeutic target

DESCRIPTION (provided by applicant): Lung transplantation remains the only therapy proven to prolong survival and improve quality of life in advanced lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). The median survival after transplantation is currently 5.3 years. Little is known about the importance and function of the lymphatic circulation after graft has been implanted and subjects develop acute and/or chronic rejection. A key question is whether post-transplantation lymphangiogenesis is beneficial (e.g. by promoting efficient inflammatory cell clearance) or detrimental (e.g. by promoting antigen presentation within draining lymph nodes and stimulating alloimmune responses). The role of the lymphatic circulation in lung allograft survival and function remains unclear. Vascular endothelial growth factor (VEGF)-C mutated at residue 156 (VEGF-C C156S) has been shown to induce lymphangiogenesis and not angiogenesis. Our preliminary data indicate that fully allogeneic murine lung grafts exhibit a decrease in the density of lymphatic vessels with acute rejection. Importantly, stimulating lymphangiogenesis after rejection has been established results in improved rejection. We hypothesize that treatment of recipient mice with VEGF-C C156S after rejection occurs will result in improved graft function by increasing clearance of pro-inflammatory pro-fibrotic molecules such as hyaluronan. To test the validity of these hypotheses, we propose the following specific aims: Aim 1: Will test the hypothesis that inducing lymphangiogenesis after established rejection will lead to decreased signs of graft rejection and improved lung function. Our working hypothesis is that VEGF-C C156S will induce lymphangiogenesis and lead to improved graft rejection and function. Our approach will include treatment of mouse transplant recipients with VEGF-C C156S, followed lung function (imaging and physiological parameters) and assess signs of rejection (histology, protein and RNA analyses). Aim 2: Will test the hypothesis that the induction of lymphangiogenesis will result in enhanced HA clearance that will lead to improved lung allograft function. Our preliminary data show that there is increased hyaluronan deposition in lung rejection. Our working hypothesis is that the induction of lymphangiogenesis will result in improved hyaluronan clearance resulting in improved lung allograft function. Our approach will include examining lung allograft hyaluronan content before and after induction of lymphangiogenesis. In addition, we will block hyaluronan clearance and assess the transplanted lung with imaging, lung physiology and histological studies. If successful, this research will provide new insights into the mechanisms underlying the influence of lymhangiogenesis on lung tissue and the role the lymphatic circulation plays in vivo in lung rejection. In addition, it will pave the way for the development of novel strategies to tret acute rejection in lung transplant recipients.

描述（由申请人提供）：肺移植仍然是唯一被证明可以延长晚期肺部疾病（如慢性阻塞性肺疾病（COPD）和特发性肺纤维化（IPF））的生存期和改善生活质量的治疗方法。目前移植后的中位生存期为5.3年。很少有人知道的重要性和功能的淋巴循环后，移植物已被植入和受试者发生急性和/或慢性排斥反应。一个关键问题是移植后淋巴管生成是有益的（例如通过促进有效的炎性细胞清除）还是有害的（例如通过促进引流淋巴结内的抗原呈递和刺激同种免疫应答）。淋巴循环在肺移植物存活和功能中的作用尚不清楚。在残基156处突变的血管内皮生长因子（VEGF）-C（VEGF-C C156 S）已显示诱导淋巴管生成而非血管生成。我们的初步数据表明，完全同种异体小鼠肺移植表现出淋巴管密度下降，急性排斥反应。重要的是，在排斥反应后刺激淋巴管生成可改善排斥反应。我们假设，在排斥发生后用VEGF-C C156 S治疗受体小鼠将通过增加促炎性促纤维化分子如透明质酸的清除来改善移植物功能。为了检验这些假设的有效性，我们提出了以下具体目标：目标1：将测试的假设，即诱导淋巴管生成后建立排斥反应将导致减少移植物排斥反应的迹象和改善肺功能。我们的工作假设是VEGF-C C156 S将诱导淋巴管生成并导致移植物排斥和功能的改善。我们的方法将包括用VEGF-C C156 S治疗小鼠移植受体，随后进行肺功能（成像和生理参数）和评估排斥反应的体征（组织学，蛋白质和RNA分析）。目标二：将检验淋巴管生成的诱导将导致HA清除增强，从而改善肺移植功能的假设。我们的初步数据显示，肺排斥反应中透明质酸沉积增加。我们的工作假设是，淋巴管生成的诱导将导致透明质酸清除率的提高，从而改善肺移植功能。我们的方法包括在诱导淋巴管生成之前和之后检查肺同种异体移植物透明质酸含量。此外，我们将阻断透明质酸清除，并通过影像学、肺生理学和组织学研究评估移植肺。如果成功，这项研究将提供新的见解的机制的影响，肺组织和淋巴循环在体内肺排斥反应中发挥的作用，hangiogenesis。此外，它将为肺移植受者急性排斥反应的治疗新策略的发展铺平道路。