THE ROLE OF ISCHEMIA REPERFUSION INJURY IN LUNG ALLOGRAFT REJECTION

描述（由申请人提供）：肺移植后的结果仍然明显比其他器官移植后的结果差。缺血再灌注损伤是肺移植术后早期发病和死亡的主要原因，也被证明是慢性肺排斥反应的危险因素，对同种异体移植物有长期影响。然而，由于缺乏肺移植生理小鼠模型，缺血再灌注损伤在调节同种异体肺移植排斥反应中的作用尚不清楚。我们实验室的新数据表明，将冷缺血从1小时延长到18小时，围手术期阻断CD154-CD40和CD28-B7通路可诱导小鼠肺同种异体移植物的急性排斥反应。这种急性排斥反应与同种异体移植物中调节性和效应性T细胞平衡的改变有关。本研究的目的是在原位小鼠肺移植模型中进行机制研究，以研究缺血再灌注损伤相关信号如何调节导致同种异体移植排斥反应的适应性免疫反应。本拨款的第一个目的是研究toll样受体信号如何调节长时间缺血后的肺同种异体移植排斥反应。第二个目的是评估与缺血再灌注损伤相关的下游炎症信号如何调节肺移植后效应T细胞和调节性T细胞之间的平衡，并控制肺移植排斥反应。我们观察到调节性T细胞与气道上皮细胞共培养后的扩增。第三个目的是研究与缺血再灌注损伤相关的信号如何调节气道上皮细胞扩增调节性T细胞的能力，以及通过与气道上皮细胞共培养扩增的调节性T细胞是否可以预防缺血再灌注损伤介导的肺同种异体移植排斥反应。公共卫生相关性：肺移植已成为终末期肺病患者的一种既定治疗方法。与心脏和肝脏等其他器官相比，肺移植后的存活率仍然相当低。肺移植成功的主要障碍是缺血再灌注损伤。我们拟利用一种新型小鼠模型研究缺血再灌注损伤对肺移植存活的影响。

DESCRIPTION (provided by applicant): Outcomes after lung transplantation remain significantly worse than after transplantation of other organs. Ischemia reperfusion injury is the leading cause for early morbidity and mortality after lung transplantation and has also been shown to be a risk factor for chronic lung rejection demonstrating its long-term effect on allografts. However, the role of ischemia reperfusion injury in regulating lung allograft rejection is not clear largely due to a lack of physiological mouse model of lung transplantation. New data from our laboratory has shown that prolonging cold ischemia from 1 hour to 18 hours induces the acute rejection of mouse lung allografts in recipients treated with perioperative blockade of CD154-CD40 and CD28-B7 pathways. This acute rejection is associated with an altered balance of regulatory and effector T cells in the allografts. The aim of this proposal is to perform mechanistic studies in the orthotopic mouse lung transplant model to investigate how ischemia reperfusion injury-associated signals regulate adaptive immune responses that lead to allograft rejection. The first aim of this grant will examine how Toll-like receptor signaling regulates lung allograft rejection after prolonged ischemia. The second aim will evaluate how downstream inflammatory signals associated with ischemia reperfusion injury regulate the balance between effector and regulatory T cells after lung transplantation and control lung allograft rejection. We observed the expansion of regulatory T cells after co-culture with airway epithelial cells. The third aim will examine how signals associated with ischemia reperfusion injury regulate the ability of airway epithelial cells to expand regulatory T cells and whether regulatory T cells, expanded through co-culture with airway epithelial cells can prevent ischemia reperfusion injury-mediated lung allograft rejection. PUBLIC HEALTH RELEVANCE: Lung transplantation has become an established therapy for patients suffering from end stage lung disease. The survival after lung transplantation remains considerably worse as compared to other organs such as the heart and the liver. A major obstacle to the success of lung transplantation is ischemia reperfusion injury. We propose to study how ischemia reperfusion injury impacts lung graft survival utilizing a novel mouse model.