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 急性肾损伤（阿基）显著增加了发生进行性肾纤维化和慢性肾纤维化的风险。 肾病（CKD）。T细胞和多形核中性粒细胞（PMNs）已被证明参与了 然而，它们在AKI向CKD转变期间的作用仍然不确定。我们最近 文献和初步数据显示，从单侧肾小管损伤中解决失败 缺血/再灌注损伤（U-IRI，一种快速AKI向CKD转变小鼠模型）不仅导致巨噬细胞 持续存在，但也有第二波T细胞和中性粒细胞浸润到肾小管上皮细胞， 与促炎环境有关与此同时，U-IRI肾组织中肾小管细胞表达较高， 损伤标志物血管细胞粘附分子1（Vcam 1）水平，并表现出去分化表达 特征，与肾脏萎缩相关。在临床上，我们发现，增加的T细胞和中性粒细胞的数量， 阿基患者肾活检时的肾结石与6个月的恢复呈负相关， GFR。在U-IRI小鼠模型中，我们发现T细胞和PMNs的耗竭减弱了第二波， 肾小管损伤和部分恢复肾小管质量，表明T细胞和中性粒细胞促进继发性肾小管损伤。 损伤和肾萎缩，阻断T细胞和PMN募集可减轻阿基所致CKD。我们 来自IRI肾脏scRNA-seq数据集的趋化因子/受体对分析鉴定了CXCL 16和 MCP-2（Ccl 8）是募集T细胞（CXCR 6+）和PMN（CCR 1+）的最高归巢信号，并且持续存在于细胞中。 巨噬细胞是AKI向CKD转变期间CXCL 16和MCP-2的主要来源。所有这些 这些发现使我们推测，在肾小管修复失败的情况下，巨噬细胞表达 CXCL 16和MCP-2促进第二波T细胞和PMN浸润到受损的肾脏中， 肾小管VCAM-1增强T细胞粘附和滞留，这一起导致继发性肾小管损伤。 因此，针对肾损伤后的CXCL 16/CXCR 6和MCP-2/CCR 1以及VCAM-1/T细胞信号传导 在治疗CKD进展方面具有巨大潜力。为了验证这一假设，我们建议定义 CXCL 16/CXCR 6和VCAM-1信号传导在T细胞归巢和粘附（SA 1）中的重要性， MCP-2/CCR 1信号转导在AKI向CKD转变过程中PMN归巢（SA 2）的重要性，然后翻译 我们对这些归巢信号的理解， 选择性地递送siRNA以敲低这些归巢信号以减缓或甚至预防CKD进展（SA 3）。 这项工作将提供临床前数据，确定如何防止第二波免疫激活， 从阿基到CKD的转变。