TIGIT in acute kidney injury and repair

TIGIT在急性肾损伤和修复中的作用

• 批准号: 10584173
• 负责人: Sanjeev Noel
• 金额: $ 50.53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584173
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adoptive Transfer; Adverse effects; Agonist; Allografting; Anti-Inflammatory Agents; Antibodies; Antibody Therapy; Apoptosis; Biopsy; Blocking Antibodies; CD4 Positive T Lymphocytes; CD8B1 gene; CTLA4 gene; Cancer Patient; Cell Separation; Cell physiology; Cells; Chronic Kidney Failure; Cisplatin; Clinical; Clinical Research; Clinical Trials; Cytometry; Data; Dendritic Cells; Development; Flow Cytometry; Functional disorder; Future; Gene Expression Profile; Genetic Transcription; Grant; Healthcare; Human; ITIM; Immune; Immune checkpoint inhibitor; Impairment; In Vitro; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Knockout Mice; Knowledge; Malignant Neoplasms; Mediating; Modeling; Mus; Natural Killer Cells; Nephrectomy; Outcome; Pathogenesis; Pathogenicity; Patients; Phase; Phenotype; Play; Process; Production; Property; Publishing; Regulatory T-Lymphocyte; Renal Cell Carcinoma; Renal function; Reperfusion Therapy; Rheumatoid Arthritis; Risk; Role; Sampling; Severity of illness; Signal Transduction; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Transplant Recipients; antagonist; anti-cancer; cancer therapy; cell type; checkpoint therapy; comparison control; cytokine; experimental study; immune checkpoint; implantation; in vivo; kidney repair; nephrotoxicity; next generation sequencing; novel; preclinical study; preimplantation; receptor; repaired; response; single-cell RNA sequencing; trafficking; transcriptome sequencing

ABSTRACT/PROJECT SUMMARY Acute kidney injury (AKI) occurs at a high rate in both native kidneys and allografts and has no specific therapy available. Prior studies have established T cell activation and trafficking as an important mechanism that modulate ischemia reperfusion (IR) and nephrotoxic AKI, along with other overlapping immune and non- immune mechanisms. Furthermore, AKI is common in patients treated with immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death receptor 1 (PD1) for multiple cancers. Our preliminary data using RNA sequencing and flow cytometry shows significant expression of novel immune checkpoint molecule, T cell immunoreceptor with Ig and ITIM domains (TIGIT) in T cells from post IR mouse kidney and ischemic human kidney. Recently published data suggest that TIGIT co-inhibitory activity modifies Th1 and Th17 responses, plus regulates Treg suppression activity. Our preliminary data shows that TIGIT expressing T cells in mouse kidney are highly activated and produce proinflammatory cytokines after IR. Importantly, mice lacking TIGIT (TIGIT KO) were protected from AKI in IR and Cisplatin AKI models, suggesting detrimental role for TIGIT during AKI. Therefore, understanding TIGIT-mediated inflammatory response during AKI is critical for developing novel AKI therapy and to mitigate kidney adverse effects of immune checkpoint therapies. The central hypothesis of this proposal is that TIGIT promotes proinflammatory functions of kidney T cells and impairs Treg suppression function. To test this hypothesis, we will (Aim 1) investigate phenotypic, functional and transcriptional effects of TIGIT in mouse kidney T cells using in vitro and in vivo approaches. We will further investigate the functional relationship between TIGIT and its co-signaling partners (CD226, CD155) and other co-inhibitory molecules (PD1, CTLA4) in regulating kidney T cell functions at baseline and during AKI. Additionally (Aim 2), we will test the hypothesis that T cell specific TIGIT activity is the major mechanism that drives AKI and impairs repair process using adoptive transfer approaches, in vivo anti-TIGIT agonist/antagonist antibody effects on AKI outcome in WT and TIGIT KO mice and blocking TIGIT signaling in repair phase after established AKI. Finally (Aim 3), we will investigate functional effects of TIGIT expression in human kidney T cells in patients with renal cell carcinoma and live donor biopsies. We will also evaluate TIGIT expression on T cells isolated from ischemic deceased donor kidney samples and transcriptional effects at single cell level in T cells from live donor kidney. Results from these studies will be the first to provide important information on TIGIT mediated effect in kidney T cell functions, therapeutic potential of targeting TIGIT for AKI treatment and set the stage for future pre-clinical and clinical studies.

摘要/项目总结 急性肾损伤（阿基）在自体肾和同种异体肾中发生率很高，并且没有特异性治疗方法 available.先前的研究已经确定T细胞活化和运输是一种重要的机制， 调节缺血再灌注（IR）和肾毒性阿基，沿着其他重叠免疫和非免疫调节， 免疫机制此外，阿基在接受免疫检查点抑制剂治疗的患者中很常见 靶向细胞毒性T淋巴细胞相关抗原4（CTLA 4）和程序性细胞死亡受体1（PD 1）， 多种癌症我们使用RNA测序和流式细胞术的初步数据显示， 在T细胞中的新型免疫检查点分子，具有IG和ITIM结构域的T细胞免疫受体（TIGIT）， IR后小鼠肾和缺血的人肾。最近发表的数据表明，TIGIT共抑制 活性修饰Th 1和Th 17应答，加上调节Treg抑制活性。我们的初步数据显示 小鼠肾脏中表达TIGIT的T细胞被高度活化并在免疫后产生促炎细胞因子。 红外光谱重要的是，在IR和顺铂阿基模型中，缺乏TIGIT的小鼠（TIGIT KO）受到保护免于阿基， 提示TIGIT在阿基期间的有害作用。因此，了解TIGIT介导的炎症 阿基期间的反应对于开发新的阿基疗法和减轻AKI期间的肾脏不良反应至关重要。 免疫检查点疗法。该提议的中心假设是TIGIT促进促炎性反应， 肾T细胞的功能和损害Treg抑制功能。为了验证这个假设，我们将（目标1） 研究TIGIT在小鼠肾T细胞中表型、功能和转录作用， in vivo体内approaches方法.我们将进一步研究TIGIT及其共信号转导之间的功能关系。 在调节肾脏T细胞功能中的CD 226、CD 155和其他共抑制分子（PD 1、CTLA 4） 在基线和阿基期间。另外（目的2），我们将检验T细胞特异性TIGIT活性是T细胞特异性TIGIT活性的假设。 体内使用过继转移方法驱动阿基并损害修复过程的主要机制 抗TIGIT激动剂/拮抗剂抗体对WT和TIGIT KO小鼠中阿基结果的作用和阻断TIGIT 在建立阿基后的修复阶段中的信号传导。最后（目的3），我们将研究TIGIT的功能效应 在肾细胞癌患者和活体供体活检中的人肾T细胞中的表达。我们还将 评估从缺血性死亡供体肾样品分离的T细胞上的TIGIT表达， 在来自活供体肾的T细胞中的单细胞水平的转录效应。这些研究的结果将是 第一次提供了关于TIGIT介导的对肾T细胞功能的作用的重要信息， 靶向TIGIT用于阿基治疗，并为未来的临床前和临床研究奠定基础。