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：
10245321
负责人：
Elizabeth A Jacobsen
金额：
$ 51.28万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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/10245321
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 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 therapeutic intervention post-transplant prevent recruit response tumor-immune system interactions

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.

项目摘要/摘要粒细胞（例如嗜酸性粒细胞）变得有害和在同种异体移植存活中均匀破坏性作用。与这个观念直接形成鲜明对比，我们的实验室使令人惊讶的是，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，我们证明了在存在联合刺激性阻滞性免疫抑制的情况下，肺同种异体移植被A迅速渗透大量可诱导的一氧化氮合酶阳性嗜酸性粒细胞。嗜酸性粒细胞的人群起着至关重要的作用在T细胞反应下调和改善移植物排斥反应中的作用。嗜酸性粒细胞的消耗植入可防止联合刺激性封锁介导的肺同种异体耐受性。这些发现导致了我们中心假设，即早期嗜酸性粒细胞进入肺部会导致同种异体移植免疫抑制通过iNOS依赖性途径。为了这一假设，我们提出了三个特定目标，以定义嗜酸性粒细胞用来诱导移植物接受的细胞机制。在AIM 1中，我们建议定义通过使用嗜酸性粒细胞特异性的iNOS途径缺陷小鼠，T细胞的NO/ROS修饰的表征以及血红素 - 氧合酶1的iNOS调节。在AIM 2中，我们将定义专业抗原呈现的作用通过测量该抑制的嗜酸性粒细胞特异性介质，嗜酸性粒细胞介导的免疫抑制的细胞树突状细胞活性，嗜酸性粒细胞和树突状细胞的双向相互作用以及突触的活成像这些细胞与T细胞之间形成。在AIM 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性封锁的效果来完成此操作在嗜酸性粒细胞趋化因子eotaxin-2上，并确定嗜酸性粒细胞募集的关键时间点使用诱导嗜酸性粒细胞耗尽小鼠的肺。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耐受性的反应，并可能阐明新型治疗的设计目前尚未探索的策略。