Protection of kidney from autoimmunity by modulating co-stimlatory signaling

项目摘要 肾脏炎症是对缺血性损伤、感染和自身反应或激活的反应 同种异体反应的淋巴细胞，导致慢性肾脏损伤、纤维化和终末期肾脏疾病。 适应性免疫反应在肾脏受到严格控制，以防止过度炎症和 保持对自身抗原的耐受性。然而，对这些机制的基本理解 支持肾脏的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方面发挥着关键作用，如 免疫检查点治疗急性间质性肾炎或移植肾排斥反应的观察 抑制剂。研究阐明了获得性免疫在肾脏炎症中的作用。然而， 抗原特异性T细胞在肾脏炎症中作用的机制研究远未完成，原因是 缺乏合适的动物模型来准确追踪抗原的特异性，这阻碍了特异性的发展 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 可在近端特异性诱导自身抗原表达的转基因小鼠模型 肾小管或足细胞，自身免疫性肾脏疾病的主要靶点。通过组合 这些动物模型使用基于四聚体的抗原特异性T细胞跟踪技术来检测内源性T细胞 识别特定多肽-MHC复合物的细胞，我们能够分析它们的表型和功能 活着。本项目的总体目标是剖析对肾功能受限的耐受机制。 抗原。我们的初步数据表明，肾脏自身抗原的特异性表达诱导了耐受 然而，给予抗PD-1和抗CTLA4可以克服这种耐受性， 主要表现为抗原特异性T细胞向肾间质的浸润。我们假设容忍度 在肾脏中是由抗原特异性T细胞表达的共刺激分子和它们的 肾实质细胞或抗原提呈细胞中发现的配体；以及耐受性的破坏 会导致肾脏的非适应性炎症。为了验证这一假设，我们将研究T细胞 稳态耐受机制(目标1)，表征肾脏浸润性致病T细胞(目标2)，以及 剖析抗原提呈细胞在耐受和自身免疫中的作用(目标3)。 这些模型为研究抗原特异性获得性免疫反应提供了一种新的创新方法。 自身免疫性肾脏疾病，并代表独特的临床前工具，这将导致识别新的 治疗靶点。此外，在完成这个K奖后，我将建立自己的翻译研究 该项目是免疫学和肾脏生物学的交叉学科。开展这一研究项目将是一个 精通特定的基础研究方法(如转录学)的绝佳机会 在肾脏生物学研究方面。

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.