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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

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.

抽象/项目总结