IL-17 and Lung Transplant Obliterative Bronchiolitis

描述(申请人提供)：与其他实体器官相比，肺移植患者的5年存活率为50%，这是由于闭塞性毛细支气管炎综合征的晚期并发症，目前还没有有效的治疗方法。闭塞性细支气管炎综合征(BOS)以呼吸道闭塞性毛细支气管炎(OB)为特征，是一种免疫介导的慢性肺排斥反应。长期目标是开发治疗OB/BOS患者的新疗法。细胞和体液自身免疫反应可以在啮齿动物模型中诱导OB，并与人类的BOS有关。被发现介导自身免疫的T细胞是产生CD4+IL-17的T细胞。这些研究表明，自身反应性Th17细胞促进了呼吸道损伤和OB。然而，IL-17介导呼吸道闭塞的机制尚不清楚。该应用的目的是确定IL-17促进肺移植闭塞性毛细支气管炎的机制。由于缺乏临床相关的OB小鼠模型，研究受到严重阻碍。我们现在已经开发出一种新的小鼠原位肺移植模型，与其他啮齿动物肺移植模型不同，它产生了与人类发现的病变相同的可重复性的呼吸道闭塞。这一应用的中心假设是由同种异体移植反应性T细胞产生的IL-17促进呼吸道纤维化。我们的假说是根据我们自己的初步数据提出的，即在我们的模型中，IL-17阻断可以防止同种异体移植物中的气道纤维化和闭塞。其具体目标是：1)确定T细胞和IL-17A或IL-17F在多大程度上是OB发生所必需的；2)确定IL-17阻断阻止OB发生的机制。这项拟议研究的基本原理是，阐明IL-17促进纤维化的机制以及阻断IL-17阻止OB的机制将为OB的治疗确定新的靶点。这项拟议的研究具有重要意义，因为它有望扩大对OB如何发展和可以预防的理解。在我们看来，这项拟议的研究是创新的，因为我们开发了一种可重复的OB临床前模型，该模型具有很高的识别新靶点进行治疗干预的可能性。

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.