Mechanisms that Promote Chronic Lung Transplant Rejection

促进慢性肺移植排斥的机制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要与其他固体器官相比收件人。支气管炎闭塞性综合征（BOS）是慢性肺移植的最常见原因拒绝。基于临床结果研究，这些研究已经确定了许多已知的非征服介体上皮损伤是BOS的危险因素，我们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识别一个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耐受性和预防闭孔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是由移植浸入驱动的效应子CD8+ T细胞抑制俱乐部细胞介导的气道上皮修复。我们实验室的新数据表明卵泡细胞毒性CD8+ T细胞，这是一个较差的CD8+ T细胞子集，在固体中无作用器官移植，可能有助于针对肺部抗原的反应。我们的小组以前有报道CCR2+单核细胞（CM）和中性粒细胞外陷阱（NET）在两个肺中起关键作用移植缺血 - 再灌注损伤和肺同种异体耐受性的诱导，但它们在耐受性的维持尚不清楚。现在，我们发现了涉及移植渗透CM的证据和OB发病机理中的网。在这里，我们建议剖析CM（AIM 1），效应器的机制 CD8+ T细胞（AIM 2）和网（AIM 3）促进OB发病机理。我们还将研究CM和网形状效应子CD8+ T细胞反应，促进OB发病机理。通过这些研究，我们希望揭示促进BOS的目标途径。