IL-17 and Lung Transplant Obliterative Bronchiolitis

IL-17 与肺移植闭塞性细支气管炎

基本信息

批准号：
8847365
负责人：
Rebecca A. Shilling
金额：
$ 39.28万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8847365
关键词：
Allografting Antigens Autoimmune Responses Autoimmunity Bone Marrow Bronchiolitis Bronchiolitis Obliterans Cells Chimera organism Chronic Collagen Complication Cystic Fibrosis Data Development Epithelial Fibrosis Goals Graft Rejection Human Immune Immunobiology Immunologist Immunology Immunosuppressive Agents Inflammatory Injury Interleukin-10 Interleukin-17 Interleukin-6 Knowledge Lesion Lung Lung Transplantation Lung diseases Mediating Mission Modeling Morbidity - disease rate Mus Obstruction Organ Outcome Pathologic Patients Pre-Clinical Model Principal Investigator Probability Process Production Public Health Pulmonary Emphysema Pulmonary Fibrosis Research Research Personnel Rodent Rodent Model Serum Signal Transduction Solid Source Survival Rate Syndrome T-Cell Immunologic Specificity T-Lymphocyte Testing Therapeutic Intervention Transplant Recipients Transplantation Work cell type clinically relevant cytokine effective therapy graft failure improved injured airway innovation lung allograft mortality mouse model novel prevent targeted treatment therapy development tool

项目摘要

DESCRIPTION (provided by applicant): The 5 year survival rate of 50% for lung transplant patients is much lower compared to other solid organs due to the late complication of bronchiolitis obliterans syndrome for which there is no effective treatment. Bronchiolitis obliterans syndrome (BOS) is characterized by obliterative bronchiolitis (OB) of the airways and is immune-mediated chronic rejection of the lung. The long-term goal is to develop novel therapies to treat patients with OB/BOS. Cellular and humoral autoimmune responses can induce OB in rodent models and are associated with BOS in humans. The T cells found to be mediating autoimmunity were CD4+ IL-17 producing T cells. These studies suggest autoreactive Th17 cells promote airway injury and OB. However, the mechanisms by which IL-17 mediates airway obliteration are not known. The objective of this application is to determine the mechanisms by which IL-17 promotes lung allograft obliterative bronchiolitis. Research has been significantly hampered by the lack of a clinically relevant murine model of OB. We have now developed a novel mouse model of orthotopic lung transplantation, which unlike other models of lung transplant in rodents, develops reproducible obliteration of the airways identical to the lesion found in humans. The central hypothesis of this application is that IL-17 produced by allograft reactive T cells promotes airway fibrosis. Our hypothesis has been formulated by our own preliminary data that IL-17 blockade prevents airway fibrosis and obliteration in allografts in our model. The specific aims are: 1) Determine the extent to which T cells and IL- 17A or IL-17F are required for the development of OB; 2) Determine mechanisms by which IL-17 blockade prevents development of OB. The rationale for the proposed research is that elucidating the mechanisms by which IL-17 promotes fibrosis and by which blockade of IL-17 prevents OB will identify novel targets for therapy for OB. The proposed research is significant because it is expected to expand understanding of how OB develops and can be prevented. In our opinion, the proposed research is innovative because we have developed a reproducible pre-clinical model of OB that has a high probability of identifying novel targets for therapeutic intervention.

描述（由申请人提供）：与其他固体器官相比，肺移植患者的5年生存率为50％，这是由于闭孔炎症综合征的晚期并发症，没有有效的治疗。支气管炎闭塞性综合征（BOS）的特征是气道的闭塞性支气管炎（OB），是免疫介导的肺部慢性排斥。长期目标是开发新的治疗OB/BOS患者的疗法。细胞和体液自身免疫反应可以在啮齿动物模型中诱导OB，并且与人类的BOS有关。发现正在介导自身免疫性的T细胞是CD4+ IL-17产生T细胞。这些研究表明自动反应性TH17细胞促进气道损伤和OB。但是，IL-17介导气道闭塞的机制尚不清楚。该应用的目的是确定IL-17促进肺同种异体移植闭孔性细支气管炎的机制。由于缺乏OB的临床相关鼠模型，研究严重阻碍了研究。现在，我们已经开发了一种新型的原位肺移植的小鼠模型，该模型与啮齿动物中的其他肺移植模型不同，它会形成与人类在人类中发现的病变相同的可再现闭塞。该应用的中心假设是同种异体移植反应性T细胞产生的IL-17促进气道纤维化。我们的假设是通过我们自己的初步数据提出的，即IL-17阻断阻止了模型中同种异体移植物中气道纤维化和闭塞。具体目的是：1）确定T细胞和IL-17A或IL-17F的发展程度； 2）确定IL-17阻滞阻止OB发展的机制。拟议的研究的基本原理是阐明IL-17促进纤维化的机制以及IL-17的阻滞阻止OB将确定OB治疗的新靶标。拟议的研究之所以重要，是因为它有望扩大对OB的发展方式和可以预防的理解。我们认为，拟议的研究具有创新性，因为我们开发了一种可再现的OB临床前模型，该模型具有很高的可能性，可以识别用于治疗干预的新目标。