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High-throughput identification and transcriptional analysis of autoreactive T cells in individuals with membranous nephropathy.

膜性肾病患者自身反应性 T 细胞的高通量鉴定和转录分析。

基本信息

批准号：
10725558
负责人：
Paolo Cravedi
金额：
$ 26.9万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-16 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725558
关键词：
Adult Affect Aftercare Alloantigen Antibodies Antigen Targeting Antigens Autoantibodies Autoimmune Autoimmune Diseases Autologous B-Lymphocytes Biological Biological Markers Blood Volume Blood specimen CD4 Positive T Lymphocytes Cell Compartmentation Cells Characteristics Circulation Clinical Clinical Research Cloning Complement Couples DNA Sequence Data Deposition Development Diagnosis Disease Disease remission End stage renal failure Epitope spreading Epitopes Exposure to Fc Receptor Functional disorder Gene Expression Profile Gene Library Generations Genetic Transcription Human Human Herpesvirus 4 Immune Tolerance Immune response Immunologic Monitoring In Vitro Individual Inflammatory Injury Libraries Link Maps Mediating Membranous Glomerulonephritis Molecular Nephrotic Syndrome Outcome Pathogenicity Pathway interactions Patients Peptide Receptor Peptides Peripheral Blood Mononuclear Cell Phospholipase Phospholipase A2 Production Receptor Cell Recombinants Renal glomerular disease Research Research Design Role Sampling Severity of illness Signal Transduction Specificity T cell regulation T cell response T-Cell Immunologic Specificity T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte T-cell receptor repertoire Techniques Technology Testing Therapeutic Therapeutic Uses Tumor Antigens United States National Institutes of Health Up-Regulation active method alpha-beta T-Cell Receptor autoreactive T cell cost effective design experience glomerular basement membrane high reward high risk innovation innovative technologies kidney biopsy novel strategies pathogen patient screening patient subsets podocyte prevent prophylactic receptor rituximab screening single-cell RNA sequencing therapeutic target tool

项目摘要

SUMMARY Membranous nephropathy (MN) is a glomerular disease due to the deposition of anti-podocyte antibodies in the subepithelial space of the glomerular basement membrane. This leadis to complement-mediated podocyte injury and, in ~30% of patients, to the development of end stage kidney disease within 10 years from diagnosis. Most of the research in MN has focused on the autoantibody specificities and has led to the identification of phospholipase 2A receptor (PLA2R) as the main target antigen in 70%-80% of the patients. Conversely, little is known on autoreactive T cells, despite the evidence from other antibody-mediated autoimmune diseases clearly showing a critical pathogenic role of autoreactive T cells, efficacy of T cell targeting treatments, and our preliminary data documenting that autoreactive T cells are present in the circulation of MN patients. Aim 1 of the present project will develop a new strategy to capture the T cell receptor (TCR) repertoire of PLA2R-reactive T cells in MN patients. We will apply high-throughput paired T cell receptor alpha and beta chain DNA sequence capture for renewable TCR gene library generation and functional screening from patient T cells. We will physically link TCR gene sequences for cloning into cellular display libraries, enabling repeated in vitro functional analyses of TCRs in ways that are impossible with alternative available techniques. Aim 2 will apply these technologies for the study of the single-cell transcriptional profile of CD4+ T cells. These data will reveal the characteristics of autoreactive TCRs in a previously collected samples from MN patients with remission versus active disease, setting the stage for expanded clinical studies. Overall, this project will collect and analyze immune response data from MN patients with unprecedented molecular scope and scale. Our approach is innovative because it couples carefully designed clinical sample sets with new high-throughput approaches in TCR analysis to comprehensively interrogate the molecular mechanisms of T cell responses in MN patients. The proposed research is significant because it will provide important tools for mechanistic studies aimed at identifying new biomarkers and therapeutic targets for MN patients.

总结