Myeloid-Derived Regulatory Cells in Asthma

哮喘中的骨髓源性调节细胞

基本信息

批准号：
9104514
负责人：
Jessy Satyadas Deshane
金额：
$ 36.25万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104514
关键词：
Adoptive Transfer Affect Allergens Antibodies Antigen Targeting Antigens Asthma Autoantibodies Autoantigens Autoimmunity Binding Biological Assay Biological Markers Bronchoalveolar Lavage CD4 Positive T Lymphocytes Cells Clinical Coculture Techniques Data Development Disease Equilibrium Free Radicals Goals HLA-DR Antigens Helper-Inducer T-Lymphocyte Human Hypersensitivity skin testing Immune Immune Tolerance Immunotherapy In Vitro Inflammation Inflammatory Inflammatory Response Laboratories Lung Mass Spectrum Analysis Mediating Modification Molecular Mus Myelogenous Nitrates Nitric Oxide Nitrogen Oxidants Oxygen Pathogenesis Pathologic Pathology Peptides Phenotype Post-Translational Protein Processing Production Proteins Public Health Reactive Nitrogen Species Recording of previous events Role Superoxides T-Cell Proliferation T-Lymphocyte T-Lymphocyte Epitopes Testing Therapeutic United States airway hyperresponsiveness airway inflammation allergic airway inflammation asthmatic asthmatic patient base disorder control immunogenic improved insight mouse model novel peripheral blood personalized medicine public health relevance response synthetic peptide

项目摘要

DESCRIPTION (provided by applicant): Objective: The goal of this proposal is to investigate the novel concept that oxidant-modified self-peptides produced by free radical producing myeloid-derived regulatory cells (MDRCs) can trigger airway hyper- responsiveness (AHR). We recently characterized MDRCs as critical regulators of airway inflammation in both mice and humans. MDRCs use reactive oxygen and reactive nitrogen species (ROS and RNS) to enhance T cell proliferation and exacerbate AHR. Our recent studies show that MDRCs induce nitrative and oxidative modifications of self-peptides which are immunogenic neo-antigens for which tolerance has not been established. Consequently, these neo-antigens can elicit pathologic inflammatory responses that represent a novel form of autoimmunity. MDRCs thus are regulators of balance between tolerance and inflammation. In Aim 1, we will identify modified self-antigens/antigenic peptides produced by pro-inflammatory airway MDRCs in asthmatics. We will determine the peptide repertoire bound to HLA-Class II molecules of O2.-- producing airway MDRCs isolated from normal and asthmatic subjects, and define the ROS- and RNS-induced modifications of these self-peptides. These studies will be conducted by eluting the Class II-bound peptides from bronchoalveolar lavage (BAL) MDRCs, and identifying the nitrative and oxidative modifications of these peptides by mass spectrometry. In Aim 2, we will determine if modified self-proteins presented by ROS- producing MDRCs in asthmatics are true neo-antigens. Peripheral blood T cells and airway MDRCs purified from healthy and asthmatic subjects, and in-vitro modified self-proteins/peptides will be used in functional assays, limiting dilution analyses and co-cultures to investigate T cell proliferative responses, clonal proliferations and Th polarization. We will use a murine model of asthma to examine molecular mechanisms of MDRC-mediated Th polarization. These studies will provide evidence of a major role for MDRCs as regulators of immune tolerance and inflammation in asthma, and elucidate a new pathogenic paradigm for asthma. Identification of post- translational modified peptide neo-antigens can help define biomarkers to characterize asthma phenotypes. These studies also have the potential to enable development of new and improved therapeutic strategies to target MDRCs for disease control of subsets of asthma phenotypes (i.e., a precision/personalized medicine approach). We will obtain insight for potential novel peptide immunotherapy strategies targeting antigen- specific T cells with novel synthetic peptides representing modified T cell epitopes. .

描述（适用提供）：目的：该提案的目的是研究新的概念，即氧化物改性的自由基生产髓样衍生的调节细胞（MDRC）可以触发气道高反应性（AHR）。最近，我们将MDRC描述为小鼠和人类气道注射的关键调节剂。 MDRC使用活性氧和活性氮（ROS和RN）来增强T细胞增殖并加剧AHR。我们最近的研究表明，MDRC会诱导自肽的硝酸和氧化修饰，这些自肽是免疫原性的新抗原，尚未确定耐受性。因此，这些新抗原可以引起代表一种新型自身免疫形式的病理炎症反应。因此，MDRC是耐受性和炎症之间平衡的调节因子。在AIM 1中，我们将确定哮喘患者促炎性气道MDRC产生的改良自我抗原/抗原宠物。我们将确定与O2的HLA级II分子结合的肽库。产生从正常和哮喘受试者分离的气道MDRC，并定义了这些自肽的ROS和RNS诱导的修饰。这些研究将通过从支气管肺泡灌洗（BAL）MDRC中解脱II类结合的宠物，并通过质谱鉴定这些肽的硝酸和氧化修饰。在AIM 2中，我们将确定通过哮喘患者中产生ROS的MDRC提出的修改的自蛋白是真正的新抗原。外周血T细胞和气道MDRC从健康和哮喘受试者中纯化，以及体外改性的自蛋白/肽将用于功能测定中，限制稀释分析和共培养，以研究T细胞增殖反应，克隆增殖和极化。我们将使用哮喘的鼠模型检查MDRC介导的TH极化的分子机制。这些研究将为MDRC作为免疫耐受性和炎症的调节剂的主要作用提供证据，并阐明哮喘的新致病范式。鉴定翻译后修饰的肽新抗原可以帮助定义生物标志物以表征哮喘表型。这些研究还有可能发展新的和改进的治疗策略，以靶向MDRC，以控制哮喘表型子集的疾病控制（即一种精确/个性化的医学方法）。我们将获得针对抗原特异性T细胞的潜在新型肽免疫疗法策略的见解，该策略具有代表修饰的T细胞表位的新型合成肽。