TIGIT in acute kidney injury and repair

TIGIT在急性肾损伤和修复中的作用

基本信息

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
项目类别：
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

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

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项目摘要

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/项目摘要急性肾脏损伤（AKI）在本地肾脏和同种异体移植物中都以高率发生，并且没有特定的治疗可用的。先前的研究已经确立了T细胞激活和运输作为一种重要机制调节缺血再灌注（IR）和肾毒性AKI，以及其他重叠的免疫和非免疫免疫机制。此外，AKI在接受免疫检查点抑制剂治疗的患者中很常见针对细胞毒性T淋巴细胞相关的抗原4（CTLA4）和程序性细胞死亡受体1（PD1）多种癌症。我们使用RNA测序和流式细胞术的初步数据显示出明显的表达新型免疫检查点分子，具有Ig和ITIM结构域（Tigit）的T细胞中T细胞中T细胞中的T细胞免疫受体 IR小鼠肾脏和缺血性人体肾脏。最近发布的数据表明Tigit共同抑制活动修改了TH1和TH17的反应，加上调节Treg抑制活性。我们的初步数据显示在小鼠肾脏中表达T细胞的Tigit高度激活，并在 ir。重要的是，缺乏Tigit的小鼠（Tigit KO）受到IR和顺铂AKI模型的AKI的保护，提示在AKI期间对Tigit的有害作用。因此，了解Tigit介导的炎症 AKI期间的反应对于开发新型AKI疗法至关重要，并减轻肾脏不良影响免疫检查点疗法。该提议的中心假设是Tigit促进促炎性肾脏T细胞的功能并损害Treg抑制功能。为了检验这一假设，我们将（目标1）使用体外和体内方法。我们将进一步研究Tigit及其共同信号之间的功能关系合作伙伴（CD226，CD155）和其他共同抑制分子（PD1，CTLA4）在调节肾脏T细胞功能中在基线和AKI期间。此外（AIM 2），我们将检验以下假设：T细胞特异性Tigit活性是使用收养转移方法驱动AKI并损害维修过程的主要机制，体内抗赋点激动剂/拮抗剂抗体对WT和Tigit KO小鼠AKI结果的影响，并阻止Tigit 建立AKI后修复阶段的信号传导。最后（AIM 3），我们将研究Tigit的功能效应肾细胞癌和活供体活检患者的人肾脏T细胞中的表达。我们也会评估从缺血死者供体肾样品中分离出的T细胞上的Tigit表达活体肾脏T细胞中单细胞水平的转录作用。这些研究的结果将是首先提供有关肾脏T细胞功能中Tigit介导的作用的重要信息，针对Tigit进行AKI治疗，并为未来的临床前和临床研究奠定了基础。