The Role of Eosinophils in the Lung Allograft

项目摘要/摘要 粒细胞，如嗜酸性粒细胞，扮演着有害的和 在同种异体肺移植存活中的一致破坏性作用。与这一概念形成鲜明对比的是，我们的实验室已经将 令人惊讶的是，嗜酸性粒细胞是同种异体肺移植耐受所必需的。具体地说，我们演示 在共刺激阻断免疫抑制存在的情况下，同种异体肺移植迅速被一种 大量诱导型一氧化氮合酶阳性的嗜酸性粒细胞。这种嗜酸性粒细胞的数量起到了关键的作用 在下调T细胞反应和改善移植物排斥反应中的作用。嗜酸性粒细胞耗尽之前 植入可防止共刺激阻断介导的同种异体肺移植耐受。这些发现导致了我们 嗜酸性粒细胞早期募集到肺导致同种异体移植免疫抑制的中心假设 通过iNOS依赖的途径。对于这一假设，我们提出了三个具体目标来定义 嗜酸性粒细胞用来诱导移植物接受的细胞机制。在目标1中，我们建议定义 诱导型一氧化氮合酶在同种异体肺移植中产生的生理及免疫抑制机制/S 嗜酸性粒细胞特异性iNOS途径缺陷小鼠，T细胞NO/ROS修饰的特征，以及 血红素加氧酶对iNOS的调节1.在目标2中，我们将定义专业抗原提呈的作用 嗜酸性粒细胞介导的免疫抑制中的细胞通过检测嗜酸性粒细胞特异性介质的抑制 树突状细胞的活性、嗜酸性粒细胞和树突状细胞的双向相互作用以及突触的实时成像 在这些细胞和T细胞之间形成。在目标3中，我们将定义有助于 嗜酸性粒细胞介导的耐受。我们将通过测量共刺激封锁的效果来完成这一点 嗜酸性粒细胞趋化因子嗜酸性粒细胞趋化因子-2的研究，以及确定嗜酸性粒细胞募集到 用可诱导的嗜酸性粒细胞耗竭小鼠肺。我们的数据将为细胞免疫提供新的见解 促进同种异体肺移植耐受的反应，并可能为设计新的治疗方法提供启示 目前还没有被探索的战略。

PROJECT SUMMARY/ ABSTRACT It has become accepted canonical dogma that granulocytes, such as eosinophils, play a deleterious and uniformly destructive role in lung allograft survival. In direct contrast to this notion our laboratory has made the surprising observation that eosinophils are essential for lung allograft tolerance. Specifically, we demonstrate that in the presence of co-stimulatory blockade immunosuppression the lung allograft is rapidly infiltrated by a high numbers of inducible nitric oxide synthase positive eosinophils. This eosinophil population plays a critical role in the downregulation of T cell responses and ameliorating graft rejection. Depletion of eosinophils prior to engraftment prevents co-stimulatory blockade-mediated lung allograft tolerance. These findings led to our central hypothesis that early recruitment of eosinophils into the lung leads to allograft immunosuppression through iNOS-dependent pathways. Towards this hypothesis we propose three Specific Aims to define the cellular mechanism used by eosinophils to induce graft acceptance. In Aim 1 we propose to define the physiology of iNOS production and mechanism/s of immunosuppression in the lung allograft through use of eosinophil-specific iNOS pathway deficient mice, characterization of NO/ROS modification of T cells, and regulation of iNOS by heme-oxygenase 1. In Aim 2 we will define the role of professional antigen presenting cells in eosinophil-mediated immunosuppression by measuring eosinophil-specific mediators of that suppress dendritic cell activity, bi-directional interactions of eosinophils and dendritic cells, and live imaging of synaptic formation between these cells with T cells. In Aim 3 we will define the migratory patterns that contribute to eosinophil-mediated tolerance. We will complete this through measuring the effect of co-stimulatory blockade on eosinophil chemokine eotaxin-2 as well as determine the critical time point of eosinophil recruitment to the lungs using inducible eosinophil depletion mice. Our data will provide novel insight into cellular immune responses contributing to lung allograft tolerance and may shed light on the design of novel therapeutic strategies that are not currently being explored.