IL-17 and Lung Transplant Obliterative Bronchiolitis

描述（申请人提供）：肺移植患者的5年生存率为50%，与其他实体器官相比，由于晚期并发症闭塞性细支气管炎综合征，没有有效的治疗方法。闭塞性细支气管炎综合征（BOS）以气道闭塞性细支气管炎（OB）为特征，是免疫介导的肺部慢性排斥反应。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在啮齿动物模型中诱导OB，并与人类BOS相关。介导自身免疫的T细胞是CD4+产生IL-17的T细胞。这些研究表明，自身反应性Th17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。本应用的目的是确定IL-17促进肺同种异体移植物闭塞性细支气管炎的机制。由于缺乏临床相关的小鼠OB模型，研究受到了很大的阻碍。我们现在开发了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，该模型与人类发现的病变相同，可形成可重复的气道闭塞。该应用的中心假设是同种异体移植物反应性T细胞产生的IL-17促进气道纤维化。我们的假设是根据我们自己的初步数据制定的，IL-17阻断可以防止同种异体移植物的气道纤维化和闭塞。具体目的是：1)确定OB的发展需要T细胞和IL- 17A或IL- 17f的程度；2)确定IL-17阻断阻止OB发展的机制。拟议研究的基本原理是阐明IL-17促进纤维化的机制，以及IL-17阻断阻止OB发展的机制，将确定OB治疗的新靶点。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，拟议的研究是创新的，因为我们已经开发了一种可重复的OB临床前模型，该模型有很高的可能性确定治疗干预的新靶点。

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.