Targeting immune dysfunction during transition from AKI to CKD

针对 AKI 向 CKD 过渡期间的免疫功能障碍

• 批准号: 10636189
• 负责人: Leyuan Xu
• 金额: $ 36.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636189
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adhesions; Atrophic; Attenuated; Bilateral; CCL8 gene; CCR1 gene; CD4 Positive T Lymphocytes; CXCR6 gene; Cell Adhesion; Cell Surface Proteins; Cells; Chronic Kidney Failure; Clinical; Contralateral; Data; Data Set; Dendrimers; Development; Disease; Disease Progression; Disease model; Exhibits; Failure; Fibrosis; Folic Acid; Functional disorder; Home; Homing; Immune; Immune System Diseases; Immune Targeting; In Vitro; Inflammation; Injury; Injury to Kidney; Ischemia; Kidney; Kidney Diseases; Knockout Mice; Lead; Macrophage; Mannose; Mediating; Modeling; Myofibroblast; Neutrophil Infiltration; Organ; PTPRC gene; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Population; Publications; Publishing; Recovery; Renal Hypertension; Reperfusion Injury; Risk; Role; Secondary to; Signal Transduction; Small Interfering RNA; Source; Stains; T cell infiltration; T-Cell Depletion; T-Lymphocyte; Testing; Time; Transgenic Mice; Translating; Tubular formation; Vascular Cell Adhesion Molecule-1; Work; cell type; chemokine; chronic infection; data repository; folate-binding protein; immune activation; improved; in vivo; inflammatory milieu; injured; innovation; interest; kidney biopsy; kidney fibrosis; kidney repair; knock-down; mannose receptor; mouse model; nanoparticle; neutralizing antibody; neutrophil; pharmacologic; pre-clinical; prevent; receptor; recruit; repaired; severe injury; siRNA delivery; single-cell RNA sequencing; targeted delivery; targeted treatment; therapeutic target

Project Summary Acute kidney injury (AKI) significantly increases the risk of developing progressive kidney fibrosis and chronic kidney disease (CKD). T cells and polymorphonuclear neutrophils (PMNs) have been shown involved in pathogenesis of AKI; however, their role(s) during AKI-to-CKD transition remain uncertain. Our recent publication and preliminary data revealed that failure of resolving tubular injury from unilateral ischemia/reperfusion injury (U-IRI, a rapid AKI-to-CKD transition mouse model) led to not only macrophage persistence but also a second wave of T cells and PMNs infiltrating into tubulointerstitium, which closely associated with a proinflammatory milieu. Concomitantly, the tubular cells from U-IRI kidney expressed higher level of injury marker, vascular cell adhesion molecule 1 (Vcam1), and exhibited a dedifferentiated expression profile, correlating with kidney atrophy. Clinically, we found that increasing numbers of T cells and PMNs in the renal interstitium at the time of renal biopsy in patients with AKI negatively correlated with 6-month recovery of GFR. In the U-IRI mouse model, we found that depletion of T cells and PMNs attenuated the second wave of tubular injury and partially restore tubule mass, suggesting that T cells and PMNs promote secondary tubular injury and kidney atrophy, and that blocking T cells and PMNs recruitment can attenuate CKD from AKI. Our chemokine/receptor pair analyses from the scRNA-seq dataset on the IRI kidneys identified that CXCL16 and MCP-2 (Ccl8) are the top homing signals to recruit T cells (CXCR6+) and PMNs (CCR1+) and that persisted macrophages are the primary source of CXCL16 and MCP-2 during AKI-to-CKD transition. Together, these findings have led us to hypothesize that in the setting of failed tubular repair, macrophage-expression of CXCL16 and MCP-2 promotes a second wave of T cells and PMNs infiltrating into the injured kidneys and that tubular VCAM-1 enhances T cells adhesion and retention, which together lead to secondary tubular injury. Thus, targeting the CXCL16/CXCR6 and MCP-2/CCR1 as well as VCAM-1/T cell signaling after kidney injury holds great potential for the treatment of CKD progression. To test this hypothesis, we propose to define the importance of CXCL16/CXCR6 and VCAM-1 signaling in T cell homing and adhesion (SA1) and the importance of MCP-2/CCR1 signaling in PMN homing (SA2) during AKI-to-CKD transition and then to translate our understanding of these homing signals into developing polyamidoamine dendrimer nanoparticles that can selectively deliver siRNAs to knockdown these homing signals to slow or even prevent CKD progression (SA3). This work will provide preclinical data defining how to prevent the second wave of immune activation and transition from AKI to CKD.

项目摘要 急性肾脏损伤（AKI）显着增加了出现进行性肾纤维化和慢性的风险 肾脏疾病（CKD）。 T细胞和多形核中性粒细胞（PMN）已显示参与 AKI的发病机理；但是，它们在AKI到CKD过渡过程中的作用仍然不确定。我们最近 出版和初步数据表明，单侧解决管状损伤的失败 缺血/再灌注损伤（U-IRI，快速AKI到CKD转变鼠标模型）不仅导致巨噬细胞 持久性，但也是第二波T细胞和PMN渗入tubulointerstitium，它们紧密 与促炎的环境有关。同时，来自U-IRI肾脏的管状细胞表达较高 损伤标记水平，血管细胞粘附分子1（VCAM1），并表现出去分化的表达 轮廓，与肾脏萎缩相关。在临床上，我们发现越来越多的T细胞和PMN在 AKI患者肾脏活检时的肾脏间质，与6个月的恢复相关 GFR。在U-IRI小鼠模型中，我们发现T细胞和PMN的耗竭减弱了第二波 管状损伤和部分恢复小管质量，表明T细胞和PMN促进了次生管状 损伤和肾脏萎缩，阻塞T细胞和PMN募集会从AKI中减弱CKD。我们的 来自IRI肾脏的SCRNA-SEQ数据集的趋化因子/受体对分析确定CXCL16和 MCP-2（CCL8）是募集T细胞（CXCR6+）和PMN（CCR1+）的最高归巢信号，并且持续存在 巨噬细胞是AKI至CKD转变期间CXCL16和MCP-2的主要来源。在一起，这些 调查结果使我们假设在失败的管状修复中，巨噬细胞表达 CXCL16和MCP-2促进了第二波T细胞，PMN浸入受伤的肾脏中， 管状VCAM-1增强T细胞的粘附和保留率，从而导致继发性管状损伤。 因此，针对CXCL16/CXCR6和MCP-2/CCR1以及肾脏损伤后VCAM-1/T细胞信号 具有巨大的CKD进展治疗潜力。为了检验这一假设，我们建议定义 CXCL16/CXCR6和VCAM-1信号在T细胞归巢和粘附（SA1）和 在AKI到CKD过渡期间，MCP-2/CCR1信号传导的重要性，然后翻译 我们对这些归巢信号的理解，用于开发可以 有选择地传递siRNA以敲除这些归巢信号以减慢甚至防止CKD进展（SA3）。 这项工作将提供临床前数据，定义如何防止第二波免疫激活和 从AKI过渡到CKD。