IL-17 and Lung Transplant Obliterative Bronchiolitis

描述（由申请人提供）：由于闭塞性细支气管炎综合征的晚期并发症，肺移植患者的5年生存率为50%，与其他实体器官相比要低得多，目前尚无有效的治疗方法。闭塞性细支气管炎综合征（BOS）是以呼吸道闭塞性细支气管炎（OB）为特征的免疫介导的肺慢性排斥反应。长期目标是开发新的疗法来治疗OB/BOS患者。细胞和体液自身免疫反应可在啮齿动物模型中诱导OB，并与人类的BOS相关。发现介导自身免疫的T细胞是产生CD 4 + IL-17的T细胞。这些研究表明，自身反应性Th 17细胞促进气道损伤和OB。然而，IL-17介导气道闭塞的机制尚不清楚。本申请的目的是确定IL-17促进肺移植物闭塞性细支气管炎的机制。由于缺乏临床相关的OB小鼠模型，研究受到严重阻碍。我们现在已经开发了一种新的小鼠原位肺移植模型，与啮齿动物中的其他肺移植模型不同，该模型产生了与人类中发现的病变相同的气道可重复闭塞。本申请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。我们的假设已经制定了我们自己的初步数据，IL-17阻断防止气道纤维化和闭塞在我们的模型中同种异体移植物。具体目标是：1）确定T细胞和IL-17 A或IL-17 F在OB发展中所需的程度; 2）确定IL-17阻断预防OB发展的机制。这项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预防OB的机制将确定OB治疗的新靶点。这项拟议中的研究意义重大，因为它有望扩大对OB如何发展和预防的理解。在我们看来，这项研究是创新的，因为我们已经开发了一种可重复的OB临床前模型，该模型很有可能确定新的治疗干预靶点。

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.