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Principal Investigator: Sanjeev Noel
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $481,466
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Acute Renal Failure with Renal Papillary Necrosis><Adoptive Transfer><Adverse effects><Agonist><Allografting><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Antibody Therapy><Apoptosis><Apoptosis Pathway><Atrophic Arthritis><Biopsy><Blocking Antibodies><CD152><CD152 Antigen><CD152 Gene><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8B><CD8B1><CD8B1 gene><CDDP><CSIF><CSIF-10><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><Cancer Patient><Cancer Treatment><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Isolation><Cell Physiology><Cell Process><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Checkpoint inhibitor><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinical><Clinical Research><Clinical Study><Clinical Trials><Cysplatyna><Cytokine Synthesis Inhibitory Factor><Cytometry><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Cytotoxic cell><Data><Dendritic Cells><Development><Dichlorodiammineplatinum><Dysfunction><Expression Signature><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Future><Gene Expression Profile><Gene Transcription><Genetic Transcription><Grant><Grawitz Tumor><Healthcare><Human><Hypernephroid Carcinoma><Hypernephroma><IL-10><IL10><IL10A><ITIM><Immune><Immune checkpoint inhibitor><Immunes><Immunoreceptor Tyrosine-Based Inhibitory Motif><Impairment><In Vitro><Inflammatory><Inflammatory Response><Injury><Interleukin 10 Precursor><Interleukin-10><Intracellular Communication and Signaling><Ischemia><K lymphocyte><KO mice><Kidney><Kidney Diseases><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Kidney Urinary System><Knock-out Mice><Knockout Mice><Knowledge><LYT3><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><NGS Method><NGS system><NK Cells><Natural Killer Cells><Nephrectomy><Nephroid Carcinoma><Nephropathy><Nephrotoxic><Null Mouse><Outcome><Pathogenesis><Pathogenicity><Patients><Peyrone's Chloride><Peyrone's Salt><Phase><Phenotype><Physiopathology><Platinum Diamminodichloride><Play><Process><Production><Programmed Cell Death><Property><Publishing><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Regulatory T-Lymphocyte><Renal Adenocarcinoma><Renal Cell Adenocarcinoma><Renal Cell Cancer><Renal Cell Carcinoma><Renal Disease><Renal Grafting><Renal Transplantation><Renal Transplants><Renal function><Reperfusion Therapy><Rheumatoid Arthritis><Risk><Role><Sampling><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Subcellular Process><T-Cell Activation><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Testing><Therapeutic><Transcription><Transplant Recipients><Treg><Veiled Cells><activate T cells><acute kidney injury><antagonism><antagonist><anti-cancer><anti-cancer therapy><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><biological signal transduction><cancer therapy><cancer-directed therapy><cell sorting><cell type><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chronic kidney disease><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><compare to control><comparison control><cytokine><cytotoxic T-lymphocyte antigen 4><developmental><disease severity><experiment><experimental research><experimental study><experiments><flow cytophotometry><gene expression pattern><gene expression signature><health care><immune check point><immune check point inhibitor><immune check point therapy><immune checkpoint><immune checkpoint therapy><immunecheckpoint><implantation><in vivo><injuries><kidney adenocarcinoma><kidney disorder><kidney function><kidney repair><kidney toxicity><kidney tx><malignancy><neoplasm/cancer><nephrotoxicity><next gen sequencing><next generation sequencing><nextgen sequencing><novel><pathophysiology><pre-clinical study><pre-implantation><preclinical study><preimplantation><receptor><regulatory T-cells><renal><renal disorder><repair><repaired><reperfusion><response><rheumatic arthritis><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><thymus derived lymphocyte><trafficking><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><transplant patient>