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Protection of kidney from autoimmunity by modulating co-stimlatory signaling

通过调节共刺激信号来保护肾脏免受自身免疫的影响

基本信息

批准号：
10614441
负责人：
Naoka Murakami
金额：
$ 16.84万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10614441
关键词：
Acute Affect Anatomy Animal Model Antibodies Antigen-Presenting Cells Antigens Autoantigens Autoimmune Autoimmunity Automobile Driving Basic Science Biology CD80 gene CTLA4 gene Cells Chronic Clinical Data Dendritic Cells Development Discipline Disease model Economic Burden Elements End stage renal failure Fibrosis Funding Genetically Engineered Mouse Goals Health Immune Tolerance Immune checkpoint inhibitor Immune response Immunology Immunosuppression Infection Infiltration Inflammation Injury Injury to Kidney Interstitial Nephritis Ischemia K-Series Research Career Programs Kidney Kidney Diseases Knowledge Ligands Lymphocyte Maintenance Mediating Modeling Nephritis PD-1/PD-L1 Pathogenicity Pathologic Processes Pathway interactions Patients Peptide/MHC Complex Persons Phenotype Play Reagent Research Research Methodology Research Project Grants Role Sampling Signal Pathway Signal Transduction Source Specificity T cell infiltration T cell therapy T-Cell Activation T-Cell Receptor T-Lymphocyte Techniques Technology Testing Tissues Transgenic Mice Transgenic Organisms Translational Research Tubular formation Tubulointerstitial Nephritis United States adaptive immune response adaptive immunity allograft rejection anti-CTLA4 anti-PD-1 anti-PD-L1 antigen-specific T cells autoreactivity cancer immunotherapy cancer transplantation career development chemokine genetic approach immune activation immunoregulation in vivo innovation ischemic injury kidney allograft mouse model new therapeutic target novel podocyte pre-clinical prevent programmed cell death ligand 1 programmed cell death protein 1 programs receptor renal damage response targeted treatment therapeutic target tool transcriptome sequencing transcriptomics

项目摘要

Project Summary Kidney inflammation occurs in response to ischemic injury, infections, and activation of autoreactive or alloreactive lymphocytes and contributes to chronic kidney damage, fibrosis and end-stage kidney diseases. Adaptive immune responses are tightly controlled in the kidney to prevent excessive inflammation and to maintain tolerance against self-antigens. However, the fundamental understanding of the mechanisms supporting immune regulation in the kidney is incomplete. Clinical observations suggest that the co-stimulatory molecules such as PD-1 and CTLA4 play pivotal roles in regulating immune responses in the kidney, as observed in acute interstitial nephritis or kidney allograft rejection in patients treated with immune checkpoint inhibitors. Studies have elucidated the contribution of adaptive immunity in kidney inflammation. However, the mechanistic study on the roles of antigen-specific T cells in kidney inflammation is far from complete due to the lack of appropriate animal models to precisely track antigen specificity and this hinders development of specific targeted therapy in autoimmune kidney diseases. To close this knowledge gap, we developed two new transgenic mouse models in which the expression of self-antigens can be specifically induced in proximal tubules or podocytes, the main target anatomical segments in the autoimmune kidney diseases. By combining these animal models with a tetramer-based antigen-specific T cell tracking technique to detect endogenous T cells that recognize specific peptide-MHC complexes, we are able to analyze their phenotype and function in vivo. The overall goal of this project is to dissect the mechanisms of tolerance against kidney-restricted antigens. Our preliminary data indicated that kidney-specific expression of self-antigens induced tolerance against these antigens; however, administration of anti-PD-1 and anti-CTLA4 could overcome the tolerance, manifested as infiltration of antigen-specific T cells into kidney interstitium. We hypothesize that the tolerance in the kidney is regulated by the co-stimulatory molecules expressed in antigen-specific T cells and their ligands found in kidney parenchymal cells or antigen presenting cells; and that disruption of the tolerance would lead to maladaptive inflammation in the kidney. To test this hypothesis, we will investigate T cell tolerance mechanism at steady state (Aim 1), characterize kidney-infiltrating pathogenic T cells (Aim 2), and dissect the roles of antigen presenting cells in tolerance and autoimmunity (Aim 3). These models provide a novel and innovative approach to study antigen-specific adaptive immune response in autoimmune kidney disease and represent unique preclinical tools, which will lead to identification of novel therapeutic targets. In addition, after completing this K award, I will establish my own translational research project in the intersection of immunology and kidney biology. Developing this research project will be an exceptional opportunity to become proficient in specific basic research methodologies (e.g. transcriptomics) and in kidney biology research.

项目总结