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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：
10660959
负责人：
LLOYD G CANTLEY
金额：
$ 49.17万
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/10660959
关键词：
3-Dimensional Acute Acute Renal Failure with Renal Papillary Necrosis Adrenal Cortex Hormones Adult Affect Animal Model Antibiotics Antibodies Antigens 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 Infiltration 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 Universities Urine Validation Virus Diseases Withdrawal adjudication adverse event risk biobank cell type clinical diagnosis cohort cytokine design eosinophil exhaust immune cell infiltrate 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，在接受肾活检的患者中，高达20%的患者发生急性肾损伤（阿基）。尽管我们目前有2种临床干预措施可用于治疗AIN患者（停用不良药物，皮质类固醇），40-60%的AIN患者继续发展为慢性肾脏疾病（CKD），即使适当对待。AIN中的肾损伤被认为是由免疫介导的肾小管损伤引起的，最终导致纤维化和永久性肾损伤近来，多种自身免疫性疾病和癌症的免疫基础的扩张导致了靶向治疗的发展，表现出改善的疗效和毒性相比，皮质类固醇因此，分析免疫浸润和产生的驻留细胞（肾小管和血管）提供了对启动和传播AIN的特异性免疫事件的病原学理解的应答应该导致开发和/或重新利用更有效地解决AIN的靶向治疗并防止进展为CKD，以及潜在的毒性较小。包括我们自己在内的几个小组的数据表明，CD 4 + T辅助细胞（特别是TH 2/TH 9）亚群）是AIN的潜在驱动因素。我们已经发现，TH 2/TH 9细胞因子IL-5和IL-9以及一些类型的细胞， 2免疫，肥大细胞和嗜酸性粒细胞，是较高的尿液或肾脏的AIN患者。基于这些数据，这是我们的假设，TH 2/TH 9 T辅助细胞在肾脏本身发挥重要的致病作用，促进AIN中的肾小管或血管损伤。我们将通过进行定量评估来检验这一假设 AIN患者肾脏免疫浸润和伴随的肾小管和血管反应。我们将使用来自两所大学健康中心的现有肾活检，由3名肾脏病理学家裁定为存在AIN 中心（耶鲁大学和约翰霍普金斯），作为本研究的发现和验证队列。进行定量分析，分析我们将使用称为成像质谱细胞术（IMC）的成像技术，在单个组织切片上对多达42种抗体进行空间保留定量。我们有一个现有的图书馆 27种经过验证的肾脏和免疫抗体，并开发了一种机器学习协议，使用IMC准确定量和定位人类肾脏中识别的所有细胞。我们将首先增加我们验证的抗体组并优化我们的IMC方案用于AIN的研究 (SA 1）。然后，我们将使用IMC来识别，量化和定位30例AIN中的免疫和驻留细胞反应。来自耶鲁大学的30例AIN和60例非AIN对照活检（发现队列），随后是30例AIN和60例非AIN 来自JHU的对照（验证队列，SA 2）。最后，我们将定义细胞决定因子之间的关系 AIN和肾功能恢复以及对类固醇的反应（SA 3）。我们的发现不仅会导致在AIN中鉴定新的可药用靶点，而且还导致改善AIN的临床组织学诊断。