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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：
9924627
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 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924627
关键词：
Adoptive Transfer Affect Allergens Antibodies Antigen Targeting Antigens Asthma Autoantibodies Autoantigens Autoimmunity Biological Assay Biological Markers Biological Response Modifiers Bronchoalveolar Lavage 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 Pathogenicity Pathologic Patients 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 antigen-specific T cells asthma model asthmatic base disorder control immunogenic immunopathology immunoregulation improved insight mouse model neoantigens 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. .