Mechanisms that Promote Chronic Lung Transplant Rejection

促进慢性肺移植排斥的机制

• 批准号: 10024446
• 负责人: Andrew Eric Gelman
• 金额: $ 39.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-12 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10024446
• 关键词: Ablation; Adoptive Transfer; Allograft Tolerance; Allografting; Alveolar Macrophages; Antibodies; Autoantigens; Autoimmune Diseases; Bone Marrow Transplantation; Bronchiolitis; Bronchiolitis Obliterans; CD8-Positive T-Lymphocytes; CD8B1 gene; CSF3 gene; Cell Proliferation; Cell Survival; Cells; Chromatin; Chronic; Clinical; Communication; Coupled; Data; Dendritic Cells; Development; Disease; Exposure to; Foundations; Functional disorder; Gastroesophageal reflux disease; Gene Targeting; Generations; Genes; Graft Rejection; Granulocyte-Macrophage Colony-Stimulating Factor; ITGAX gene; Immune; Immunologics; Impairment; Infection; Inflammatory; Interferon Type I; Ischemia; Joints; Laboratories; Left; Lesion; Life; Longevity; Lung; Lung Transplantation; Lung diseases; MHC Class I Genes; Maintenance; Mediating; Mediator of activation protein; Methods; Modeling; Mus; Natural Killer Cells; Operative Surgical Procedures; Organ; Organ Transplantation; Outcome Study; Pathogenesis; Pathologic; Pathway interactions; Patients; Play; Prevention; Process; Regimen; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Risk; Risk Factors; Role; Shapes; Solid; Stress; Syndrome; T cell response; T-Lymphocyte Subsets; Techniques; Toxic Environmental Substances; Transforming Growth Factor beta; Transplantation; Transplantation Tolerance; adaptive immune response; airway epithelium; autoreactivity; base; cell regeneration; cytotoxic CD8 T cells; effector T cell; epithelial injury; epithelial stem cell; extracellular; functional loss; improved; innovation; lung allograft; macrophage; monocyte; neutrophil; novel; novel strategies; pathogen; prevent; progenitor; repaired; response; trafficking; transplant model; treatment strategy

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.

项目总结/摘要 与其他实体器官相比，肺受体的寿命较短，排斥率较高 受惠人士闭塞性细支气管炎综合征（BOS）是慢性肺移植最常见的原因 排斥反应基于临床结果研究，已经确定了许多已知的非同种免疫介质， 上皮损伤作为BOS的危险因素，我们已经开发了一种新的小鼠原位肺移植模型， 概括了这种关系。这项创新使我们能够鉴定出一种关键的气道上皮细胞祖细胞， 俱乐部细胞对于维持同种异体移植物耐受性和预防闭塞性细支气管炎至关重要 (OB)- BOS的主要病理指标。我们还观察到OB是由移植物浸润 抑制棒状细胞介导的气道上皮修复的效应CD 8 + T细胞。我们实验室的新数据 提示滤泡细胞毒性CD 8 + T细胞，一种定义不明确的CD 8 + T细胞亚群，在实体瘤中没有报道作用， 器官移植可以促进针对肺自身抗原的应答。我们的团队以前 报道CCR 2+单核细胞（CM）和中性粒细胞胞外陷阱（NET）在两个肺中起关键作用， 移植物缺血-再灌注损伤和诱导肺移植耐受，但它们的作用， 耐受性的维持仍不清楚。我们现在发现的证据表明移植物渗入CM NET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 CD 8 + T细胞（Aim 2）和NET（Aim 3）促进OB发病。我们还将研究CM和NET如何 形成效应CD 8 + T细胞反应，促进OB发病机制。通过这些研究，我们希望 揭示促进BOS的靶向途径。