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Defining the Pathogenesis and Prognosis of Human Acute Interstitial Nephritis

人类急性间质性肾炎的发病机制和预后的定义

基本信息

批准号：
10264054
负责人：
LLOYD G CANTLEY
金额：
$ 52.86万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10264054
关键词：
3-Dimensional Acute Acute Renal Failure with Renal Papillary Necrosis Adrenal Cortex Hormones Adult Affect Animal Model Antibiotics Antibodies Antigens Archives Autoimmune Diseases Biopsy Biopsy Specimen Blood Blood Vessels CD4 Positive T Lymphocytes Cell Communication Cells Characteristics Chronic Kidney Failure Clinical Clinical Data Cohort Studies Cytometry Data Delayed Hypersensitivity Development Diagnosis Drug Exposure Evaluation Event Exhibits Fibrosis Formalin Health Helper-Inducer T-Lymphocyte Histologic Human Image Imaging Techniques Immune Immune checkpoint inhibitor Immune response Immunity Infection Inflammation Inflammation Mediators Injury Interleukin-5 Interleukin-9 Interstitial Nephritis Intervention Kidney Lead Left Libraries Location Lung Machine Learning Malignant Neoplasms Mediating Neighborhoods Optics Organ Paraffin Embedding Participant Pathogenesis Pathogenicity Pathologic Patients Pharmaceutical Preparations Play Prognosis Protocols documentation Proton Pump Inhibitors Quantitative Evaluations Reaction Recovery Recovery of Function Renal function Role Sampling Site Skin Source Steroids Techniques Testing Tissue Preservation Tissues Toxic effect Tubular formation Tumor-infiltrating immune cells Universities Urine Validation Virus Diseases Withdrawal adjudicate adverse event risk base biobank cell type clinical Diagnosis cohort cytokine design eosinophil exhaust improved injured kidney biopsy kidney dysfunction mast cell multiphoton imaging new therapeutic target novel preservation prevent renal damage response single-cell RNA sequencing targeted treatment vascular injury

项目摘要

Acute interstitial nephritis (AIN), resulting from drug exposure, infection or autoimmune disease, is the cause of acute kidney injury (AKI) in up to 20% of patients who undergo a kidney biopsy. Even though we currently have 2 clinical interventions available to treat patients with AIN (withdrawal of the offending drug and corticosteroids), 40-60% of patients with AIN go on to develop chronic kidney disease (CKD) even when appropriately treated. Kidney damage in AIN is believed to result from immune-mediated tubular injury that eventually leads to fibrosis and permanent kidney damage. The recent dileniation of the immune underpinnings of multiple autoimmune diseases and cancers has led to the development of targeted therapies that exhibit improved efficacy and less toxicity compared to corticosteroids. Therefore, an analysis of the immune infiltrate and resulting resident cell (tubular and vascular) responses that provides pathogenic understanding of the specific immune events that initiate and propogate AIN should lead to development and/or repurposing of targeted therapies that are more effective at resolving AIN and preventing the progression to CKD, as well as potentially less toxic. Data from several groups, including our own, suggest that CD4+ T-helper cells (particularly the TH2/TH9 subsets) are potential drivers of AIN. We have found that TH2/TH9 cytokines IL-5 and IL-9 and some cells of type 2 immunity, mast cells and eosinophils, are higher in the urine or kidneys of patients with AIN. Based on these data, it is our hypothesis that TH2/TH9 T-helper cells in the kidney itself play an important pathogenic role in promoting tubular or vascular injury in AIN. We will test this hypothesis by performing a quantitative evaluation of the kidney immune infiltrate and accompanying tubular and vascular response in humans with AIN. We will use existing kidney biopsies, adjudicated by 3 nephropathologists as exhibiting AIN, from two university health centers (Yale and Johns Hopkins), as discovery and validation cohorts for this study. To perform the quantitative analysis we will use an imaging technique called Imaging Mass Cytometry (IMC) that supports the simultaneous, spatially-preserved quantification of up to 42 antibodies on a single tissue section. We have an existing library of 27 validated kidney and immune antibodies and have developed a machine learning protocol to rapidly and accurately quantify and localize all cells in the human kidney identified using IMC. We will first increase our validated antibody panel and optimize our IMC protocol for use in the study of AIN (SA 1). We will then use IMC to identify, quantify and localize the immune and resident cell responses in 30 AIN cases and 60 non-AIN control biopsies from Yale (discovery cohort), followed by 30 AIN cases and 60 non-AIN controls from JHU (validation cohort, SA 2). Finally, we will define the relationship between cellular determinants of AIN and recovery of kidney function as well as response to steroids (SA3). Our findings will not only lead to identification of novel druggable targets in AIN, but also lead to improving clinical histological diagnosis of AIN.

急性间质性肾炎（AIN）是由药物暴露、感染或自身免疫性疾病引起的