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

• 批准号: 10397065
• 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
• 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/10397065
• 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; 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; Persons; 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

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.

项目概要 肾脏炎症是由于缺血性损伤、感染和自身反应性或自身反应性的激活而发生的。 同种异体反应性淋巴细胞，导致慢性肾损伤、纤维化和终末期肾病。 适应性免疫反应在肾脏中受到严格控制，以防止过度炎症并 保持对自身抗原的耐受性。然而，对机制的基本了解 肾脏的支持免疫调节是不完整的。临床观察表明，共刺激 PD-1 和 CTLA4 等分子在调节肾脏免疫反应中发挥着关键作用， 在接受免疫检查点治疗的患者中观察到急性间质性肾炎或肾同种异体移植排斥反应 抑制剂。研究阐明了适应性免疫在肾脏炎症中的作用。然而， 由于抗原特异性 T 细胞在肾脏炎症中作用的机制研究还远未完成 缺乏适当的动物模型来精确追踪抗原特异性，这阻碍了特异性抗原的开发 自身免疫性肾脏疾病的靶向治疗。为了缩小这一知识差距，我们开发了两种新的 转基因小鼠模型，其中自身抗原的表达可以在近端特异性诱导 肾小管或足细胞是自身免疫性肾脏疾病的主要目标解剖部分。通过结合 这些动物模型采用基于四聚体的抗原特异性 T 细胞追踪技术来检测内源性 T 识别特定肽-MHC 复合物的细胞，我们能够分析它们的表型和功能 体内。该项目的总体目标是剖析肾限制性肾病的耐受机制 抗原。我们的初步数据表明，自身抗原的肾脏特异性表达诱导耐受 针对这些抗原；然而，给予抗PD-1和抗CTLA4可以克服耐受性， 表现为抗原特异性T细胞浸润肾间质。我们假设耐受性 肾脏中的免疫调节受到抗原特异性 T 细胞中表达的共刺激分子及其调节 肾实质细胞或抗原呈递细胞中发现的配体；以及耐受性的破坏 会导致肾脏出现适应不良炎症。为了验证这个假设，我们将研究 T 细胞 稳态耐受机制（目标 1），表征肾脏浸润致病性 T 细胞（目标 2），以及 剖析抗原呈递细胞在耐受和自身免疫中的作用（目标 3）。 这些模型提供了一种新颖且创新的方法来研究抗原特异性适应性免疫反应 自身免疫性肾病并代表独特的临床前工具，这将导致识别新的 治疗目标。另外，完成这个K奖后，我将建立自己的转化研究 免疫学和肾脏生物学交叉项目。开发这个研究项目将是 精通特定基础研究方法（例如转录组学）的绝佳机会 以及肾脏生物学研究。