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：
9908074
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908074
关键词：
Acute Affect Anatomy Animal Model Antibodies Antigen-Presenting Cells Antigens Autoantigens Autoimmune Process 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 Immune Tolerance Immune checkpoint inhibitor Immune response Immunology Immunosuppression Infection Infiltration Inflammation Injury Injury to Kidney Interstitial Nephritis K-Series Research Career Programs Kidney Kidney Diseases Knowledge Lead Ligands Lymphocyte Maintenance Mediating Modeling Nephritis PD-1/PD-L1 Pathogenicity Pathologic Processes Pathway interactions Patients Peptide/MHC Complex Phenotype Play Reagent Research Research Methodology Research Project Grants Role Sampling Signal Pathway Signal Transduction Source Specificity T cell therapy T-Cell Activation T-Cell Receptor T-Lymphocyte Techniques Testing Tissues Transgenic Mice Transgenic Organisms Translational Research Tubular formation Tubulointerstitial Nephritis Tumor-infiltrating immune cells United States adaptive immune response adaptive immunity allograft rejection anti-CTLA4 anti-PD-1 anti-PD-L1 antigen-specific T cells autoreactivity base cancer immunotherapy cancer transplantation career development chemokine genetic approach health economics 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.

项目摘要肾脏炎症是由于缺血性损伤，感染和自动反应性或激活而发生的同种异体淋巴细胞，并导致慢性肾脏损伤，纤维化和终末期肾脏疾病。自适应免疫反应在肾脏中受到严格控制，以防止过度炎症和保持对自我抗原的容忍度。但是，对机制的基本理解支持肾脏中的免疫调节是不完整的。临床观察表明共同刺激 PD-1和CTLA4等分子在调节肾脏的免疫反应中起关键作用，如在接受免疫检查点治疗的患者中观察到的急性间质性肾炎或肾脏同种异体移植排斥抑制剂。研究阐明了适应性免疫在肾脏炎症中的贡献。但是，关于抗原特异性T细胞在肾脏炎症中的作用的机理研究远非完整缺乏适当的动物模型来精确跟踪抗原特异性，这阻碍了特定的发展自身免疫性肾脏疾病的靶向疗法。为了缩小这一知识差距，我们开发了两个新的转基因小鼠模型，其中可以在近端特别诱导自抗原的表达小管或足细胞，这是自身免疫肾脏疾病中的主要目标解剖片段。通过组合这些动物模型具有基于四聚体的抗原特异性T细胞跟踪技术，可检测内源性T 识别特定肽-MHC复合物的细胞，我们能够分析其表型和功能体内。该项目的总体目标是剖析针对肾脏受限的耐受性机制抗原。我们的初步数据表明，自我抗原诱导耐受性的肾脏特异性表达反对这些抗原；但是，抗PD-1和抗CTLA4的给药可以克服公差，表现为将抗原特异性T细胞浸润到肾脏间质中。我们假设公差在肾脏中，在抗原特异性T细胞中表达的共刺激分子及其调节在肾实质细胞或抗原呈递细胞中发现的配体；宽容的破坏会导致肾脏适应不良的炎症。为了检验该假设，我们将研究T细胞稳态的耐受性机制（AIM 1），表征肾脏渗透的致病性T细胞（AIM 2），并且剖析抗原呈现细胞在耐受性和自身免疫性中的作用（AIM 3）。这些模型提供了一种新颖而创新的方法来研究抗原特异性适应性免疫反应自身免疫性肾脏疾病并代表独特的临床前工具，这将导致新颖的鉴定治疗靶标。此外，完成该K奖后，我将建立自己的翻译研究免疫学与肾脏生物学交集的项目。开发该研究项目将是精通特定基础研究方法（例如转录组学）的杰出机会和肾脏生物学研究。