Mechanisms that Promote Chronic Lung Transplant Rejection

项目摘要/摘要 与其他实体器官相比，肺移植受者的寿命更短，排斥率更高 收件人。闭塞性细支气管炎综合征(BOS)是慢性肺移植最常见的原因 拒绝。基于已确定许多已知的非同种异体免疫介质的临床结果研究 作为BOS的危险因素，我们开发了一种新的小鼠原位肺移植模型，该模型 重述了这种关系。这项创新使我们能够识别关键的呼吸道上皮细胞前体细胞， 对于维持同种异体移植耐受和预防闭塞性毛细支气管炎至关重要的俱乐部细胞 (OB)--BOS的主要病理指标。我们还观察到OB是由移植物渗透驱动的 抑制杆状细胞介导的呼吸道上皮修复的效应CD8+T细胞。来自我们实验室的新数据 提示滤泡细胞毒性CD8+T细胞，一个定义不明确的CD8+T细胞亚群，在固体中的作用未见报道 器官移植，可能有助于对肺自身抗原的反应。我们小组之前已经 据报道，CCR2+单核细胞(CM)和中性粒细胞胞外陷阱(Net)在两个肺中都起着关键作用 移植肺缺血再灌注损伤及诱导同种异体肺移植耐受 耐受性的维持仍不明朗。我们现在发现了涉及移植物渗入CM的证据 NETs在OB发病机制中的作用。在这里，我们建议剖析CM(目标1)、效应器 CD8+T细胞(Aim 2)和Net(Aim 3)促进OB的发病。我们还将研究CM和Net如何 促进OB发病的形状效应CD8+T细胞反应。通过这些研究，我们期望 揭示促进BOS的有针对性的途径。

PROJECT SUMMARY/ABSTRACT Lung recipients suffer from shorter life spans and higher rejection rates when compared to other solid organ recipients. Bronchiolitis obliterans syndrome (BOS) is the most common cause of chronic lung transplant rejection. Based on clinical outcome studies that have identified many known non-alloimmune mediators of epithelial injury as risk factors for BOS, we have developed a new mouse orthotopic lung transplant model that recapitulates this relationship. This innovation has allowed us to a identify a key airway epithelial cell progenitor, the club cell, as vital for the maintenance of allograft tolerance and the prevention of obliterative bronchiolitis (OB) - the major pathological indicator of BOS. We have also observed that OB is driven by graft-infiltrating effector CD8+ T cells that inhibit club cell-mediated repair of airway epithelium. New data from our laboratory suggests that follicular cytotoxic CD8+ T cells, a poorly defined CD8+ T cell subset with no reported role in solid organ transplantation, may facilitate responses against pulmonary-self antigens. Our group has previously reported that CCR2+ monocytes (CM) and neutrophil extracellular traps (NETs) play critical roles in both lung transplant ischemia-reperfusion injury and the induction of lung allograft tolerance, but their role in the maintenance of tolerance remains unclear. We have now uncovered evidence implicating graft-infiltrating CM and NETs in OB pathogenesis. Here we propose to dissect the mechanisms by which CM (Aim 1), effector CD8+ T cells (Aim 2) and NETs (Aim 3) promote OB pathogenesis. We will also examine how CM and NETs shape effector CD8+ T cell responses that promote OB pathogenesis. Through these studies, we expect to reveal targetable pathways that promote BOS.