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(AKI)显著增加发生进行性肾纤维化和慢性肾功能衰竭的风险 肾病(CKD)。T细胞和中性粒细胞(PMN)已被证明参与了 AKI的发病机制；然而，他们在AKI到CKD转变过程中的作用(S)仍然不确定。我们最近 文献和初步数据显示，单侧肾小管损伤的解决失败 缺血/再灌注损伤(U-IRI，一种从AKI到CKD的快速过渡小鼠模型)不仅导致巨噬细胞 持续，但也有第二波T细胞和PMN渗入肾小管间质，这与 与促炎环境有关。同时，U-IRI肾小管上皮细胞表达较高 损伤标志物血管细胞黏附分子1(Vcam1)水平，并呈现去分化表达 与肾脏萎缩相关的侧写。临床上，我们发现T细胞和中性粒细胞数量的增加。 AKI患者肾活检时肾间质与肾功能恢复呈负相关 GFR。在U-IRI小鼠模型中，我们发现T细胞和PMN的耗尽减弱了第二波 肾小管损伤和部分肾小管质量恢复，提示T细胞和中性粒细胞促进继发性肾小管损伤 损伤和肾脏萎缩，阻断T细胞和PMN募集可以减轻AKI所致的CKD。我们的 来自IRI肾脏的scRNA-seq数据集的趋化因子/受体对分析表明，CXCL16和 MCP-2(Ccl8)是招募T细胞(CXCR6+)和中性粒细胞(CCR1+)的最高归巢信号，并且持续存在 在AKI向CKD转化过程中，巨噬细胞是CXCL16和MCP-2的主要来源。加在一起，这些 这些发现使我们假设，在肾小管修复失败的情况下，巨噬细胞表达 CXCL16和MCP-2促进第二波T细胞和中性粒细胞渗入受损肾脏 肾小管VCAM-1促进T细胞的黏附和滞留，共同导致继发性肾小管损伤。 因此，肾损伤后靶向CXCL16/CXCR6和MCP-2/CCR1以及VCAM-1/T细胞信号转导 对CKD进展期的治疗具有巨大的潜力。为了检验这一假设，我们建议定义 CXCL16/CXCR6和VCAM-1信号在T细胞归巢和黏附中的重要性 MCP-2/CCR1信号在AKI向CKD转变过程中PMN归巢(SA2)及其翻译中的重要性 我们对这些归巢信号的理解转化为开发聚酰胺胺树枝状分子纳米颗粒，这种纳米颗粒可以 选择性地传递siRNA来敲除这些归巢信号，以减缓甚至阻止CKD的进展(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。