THE ROLE OF ISCHEMIA REPERFUSION INJURY IN LUNG ALLOGRAFT REJECTION

描述（由申请人提供）：肺移植后的结局仍明显差于其他器官移植后。缺血再灌注损伤是肺移植后早期发病率和死亡率的主要原因，也已被证明是慢性肺排斥反应的危险因素，表明其对同种异体移植物的长期影响。然而，由于缺乏生理性小鼠肺移植模型，缺血再灌注损伤在肺移植排斥反应中的作用尚不清楚。来自我们实验室的新数据表明，在接受围手术期阻断CD 154-CD 40和CD 28-B7通路治疗的受者中，将冷缺血时间从1小时延长至18小时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T细胞和效应性T细胞的平衡改变有关。本提案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。这项资助的第一个目标是研究Toll样受体信号传导如何调节长期缺血后的肺移植排斥反应。第二个目标将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T细胞之间的平衡并控制肺移植排斥反应。我们观察了与气道上皮细胞共培养后调节性T细胞的扩增。第三个目标将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既定治疗方法。肺移植后的存活率与其他器官如心脏和肝脏相比仍然相当差。肺移植成功的主要障碍是缺血再灌注损伤。我们建议利用一种新的小鼠模型研究缺血再灌注损伤如何影响肺移植物存活。

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.