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. .
The proposed studies will establish myeloid-derived regulatory cells (MDRCs) as important regulators of human asthmatic inflammation and help develop therapeutic strategies to target MDRCs for disease control of subsets of asthma phenotypes. New paradigms on pathogenesis of asthma will be established based on a major role for MDRCs as regulators of balance between immune tolerance and inflammation. Successful completion of these studies may help define biomarkers to characterize asthma phenotypes and provide new insights for development of potential novel peptide immunotherapy strategies targeting antigen-specific T cells with novel synthetic peptides representing modified T cell epitopes.
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