The Role of Eosinophils in the Lung Allograft

嗜酸性粒细胞在同种异体肺移植物中的作用

基本信息

批准号：
9757854
负责人：
Elizabeth A Jacobsen
金额：
$ 53.94万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757854
关键词：
Allograft Tolerance Allografting Antigen-Presenting Cells Arginine Attenuated Biology CD8-Positive T-Lymphocytes Cell Communication Cell Differentiation process Cell physiology Cells Data Dendritic Cells Down-Regulation Engraftment Eotaxin Failure Goals Graft Rejection Human ITGAX gene Image Immune Immune response Immune system Immunologics Immunology Immunosuppression Immunosuppressive Agents In Vitro Interleukin 2 Receptor Interleukin-2 Laboratories Light Lung Lung Transplantation Maintenance Measures Mediating Mediator of activation protein Metabolism Modification Mus Myeloid Cells NOS2A gene Nitric Oxide Organ Organ Survival Organ Transplantation Pathway interactions Patients Pattern Pharmaceutical Preparations Physiology Play Population Post-Translational Protein Processing Pre-Clinical Model Production Professional Role Reactive Oxygen Species Receptor Signaling Role Signal Transduction Small inducible cytokine A24 Solid Source Starvation Synapses T cell differentiation T cell regulation T cell response T memory cell T-Cell Depletion T-Cell Proliferation T-Lymphocyte Testing Time Translating Transplant Recipients Transplantation Work base cell type chemokine critical period design effector T cell eosinophil granulocyte heme oxygenase-1 improved insight lung allograft macrophage mouse model novel novel therapeutics post-transplant prevent recruit response

项目摘要

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.

项目概要/摘要粒细胞（如嗜酸性粒细胞）发挥着有害且有害的作用，这已成为公认的教条。对肺同种异体移植物的存活具有一致的破坏作用。与这个概念形成直接对比的是，我们的实验室已经做出了令人惊讶的观察结果是，嗜酸性粒细胞对于肺同种异体移植耐受至关重要。具体来说，我们证明在存在共刺激阻断免疫抑制的情况下，同种异体肺移植物迅速被大量诱导型一氧化氮合酶阳性嗜酸性粒细胞。这个嗜酸性粒细胞群体起着至关重要的作用下调 T 细胞反应和改善移植排斥反应中的作用。之前消耗嗜酸性粒细胞植入可防止共刺激阻滞介导的肺同种异体移植耐受。这些发现导致我们中心假设是嗜酸性粒细胞早期募集到肺部会导致同种异体移植免疫抑制通过 iNOS 依赖性途径。针对这一假设，我们提出了三个具体目标来定义嗜酸性粒细胞用于诱导移植物接受的细胞机制。在目标 1 中，我们建议定义 iNOS 产生的生理学和通过使用肺同种异体移植物进行免疫抑制的机制嗜酸性粒细胞特异性 iNOS 通路缺陷小鼠，T 细胞 NO/ROS 修饰的表征，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呈递的作用通过测量嗜酸性粒细胞特异性介质来抑制嗜酸性粒细胞介导的免疫抑制树突状细胞活性、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这些细胞与 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性。我们将通过测量共刺激阻断的效果来完成这一任务对嗜酸性粒细胞趋化因子eotaxin-2的影响以及确定嗜酸性粒细胞募集至嗜酸性粒细胞的关键时间点使用诱导型嗜酸性粒细胞耗竭小鼠的肺。我们的数据将为细胞免疫提供新的见解有助于肺同种异体移植耐受的反应，并可能为新型治疗方法的设计提供启示目前尚未探索的策略。