The Role of Neutrophils in Regulating Lung Transplant Tolerance

中性粒细胞在调节肺移植耐受中的作用

• 批准号: 8855046
• 负责人: Andrew Eric Gelman
• 金额: $ 36.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8855046
• 关键词: Acute; Antigen-Presenting Cells; Attenuated; BLR1 gene; Bronchiolitis Obliterans; Bronchus-Associated Lymphoid Tissue; CD11c Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cause of Death; Cells; Chromatin; Chronic; Clinical; Data; Development; Epithelial; Epithelial Cells; Excision; Exposure to; Functional disorder; Generations; Home environment; Homing; Human; ITGAX gene; Imaging Techniques; Immune response; Immunosuppression; Infection; Injury; Interleukin-10; Laboratories; Life; Longevity; Lung; Lung Transplantation; Lung diseases; Lymphoid; Maintenance; Mediating; Memory; Microscopy; Modeling; Mus; N-Formylated Peptide; Neutrophilia; Organ; Organ Transplantation; Pathway interactions; Patients; Pattern; Peptide Receptor; Production; Regulatory T-Lymphocyte; Reperfusion Injury; Reporting; Role; Shapes; Solid; Staging; Syndrome; T-Lymphocyte; Testing; Tissues; Transplant Recipients; Transplantation; Work; adaptive immunity; airway epithelium; cell injury; extracellular; injured; injured airway; innate immune function; intravital imaging; lung allograft; lung injury; mouse development; mouse model; neutrophil; novel; prevent; response; trafficking; two-photon

PROJECT SUMMARY/ABSTRACT Lung recipients suffer from shorter life spans and higher rejection rates when compared to other solid organ recipients. Neutrophilia is associated with graft injury but it remains unclear how neutrophils regulate adaptive immune response that control lung transplant tolerance. Recent reports from our laboratory show neutrophils trigger acute rejection by direct interactions between CD11c+ antigen presenting cells and T lymphocytes. However, how neutrophils control chronic rejection, the major cause of death of lung recipients who have had their grafts for more than one year, remains largely unknown. Using a new model of mouse orthotopic lung transplantation and novel intravital imaging techniques new data from our lab indicates that both high neutrophilia and the complete lack of neutrophils promotes chronic rejection in response to airway epithelial injury. Moreover, neutrophils are required to induce immunosuppression-mediated tolerance. In this proposal we will define mechanisms by which neutrophils differentially regulate rejection and tolerance. We have 3 specific aims. In Aim 1 we will define neutrophil activity that promotes tolerance through analyzing trafficking patterns that promote the removal of injured cells, which we hypothesize prevents chronic rejection. We also determine if the homing of central memory CD8+ T cells to lung allografts, which we have recently shown promotes the induction of immunosuppression-mediated tolerance, is dependent on neutrophils. In Aim 2 we hypothesize that high neutrophilia triggers chronic rejection through altering the stability of bronchus associated lymphoid tissue, an ectopic lymphoid aggregates that we have shown is associated with tolerance. In Aim 3, we determine if neutrophils extracellular trap (NET) generation is associated with worse primary graft dysfunction in clinical lung transplant recipients and chronic rejection in the mouse lung transplant model.

项目摘要/摘要 与其他固体器官相比 收件人。中性粒细胞与移植损伤有关，但尚不清楚中性粒细胞如何调节适应性 控制肺移植耐受性的免疫反应。我们实验室的最新报告显示中性粒细胞 通过CD11C+抗原呈递细胞和T淋巴细胞之间的直接相互作用引发急性排斥。 但是，中性粒细胞如何控制慢性拒绝，这是肺肺接受者的主要死亡原因 他们的移植物超过一年，仍然很少知道。使用鼠标原位肺的新模型 移植和新型浸润成像技术来自我们实验室的新数据表明，这两者都很高 嗜中性粒细胞和完全缺乏中性粒细胞会促进慢性拒绝，以响应气道上皮 受伤。此外，需要中性粒细胞诱导免疫抑制介导的耐受性。在此提案中 我们将定义中性粒细胞差异调节排斥和耐受性的机制。我们有3个 具体目标。在AIM 1中，我们将定义中性粒细胞活性，该活动通过分析贩运来促进公差 促进受伤细胞去除的模式，我们假设这阻止了慢性排斥。我们也是 确定中央记忆CD8+ T细胞是否将其归为肺同种异体移植物，我们最近显示了 促进免疫抑制介导的耐受性的诱导取决于中性粒细胞。在目标2中我们 假设高性嗜中性粒细胞通过改变支气管的稳定性触发了慢性排斥反应 相关的淋巴组织，我们所显示的异位淋巴聚集体与耐受性有关。 在AIM 3中，我们确定嗜中性粒细胞细胞外陷阱（净）的产生是否与较差的原发性移植有关 临床肺移植受者的功能障碍和小鼠肺移植模型中的慢性排斥反应。