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：
10096452
负责人：
LLOYD G CANTLEY
金额：
$ 56.45万
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/10096452
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 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 outcome forecast 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）是由于药物暴露，感染或自身免疫性疾病引起的多达20％的肾脏活检的患者中，急性肾脏损伤（AKI）。即使我们目前有2种临床干预措施可用于治疗AIN患者（戒断犯罪药物和皮质类固醇），40-60％的AIN患者继续发展慢性肾脏疾病（CKD）适当治疗。据信，AIN中的肾脏损伤是由免疫介导的管状损伤造成的最终导致纤维化和永久性肾脏损伤。最近对多种自身免疫性疾病和癌症的免疫基础的衰减导致了与相比皮质类固醇。因此，分析免疫浸润和由此产生的居民细胞（管状和血管）对启动和渐造AIN的特定免疫事件的致病理解的反应应导致更有效解决AIN的目标疗法的开发和/或重新利用并防止进展到CKD，并可能毒性较小。来自包括我们自己在内的几个组的数据表明CD4+ T-Helper细胞（尤其是TH2/TH9 子集）是AIN的潜在驱动因素。我们发现Th2/Th9细胞因子IL-5和IL-9以及某些类型的细胞 2免疫，肥大细胞和嗜酸性粒细胞在AIN患者的尿液或肾脏中更高。基于这些数据，我们的假设是，肾脏中的Th2/Th9 t-helper细胞本身在促进AIN中的管状或血管损伤。我们将通过进行定量评估来检验这一假设肾脏免疫浸润以及AIN人类伴随的管状和血管反应。我们将使用现有的肾脏活检，由两名大学健康的3名肾病学家裁定为展示AIN 中心（耶鲁大学和约翰·霍普金斯），作为这项研究的发现和验证人群。执行定量分析我们将使用一种称为成像质量细胞术（IMC）的成像技术，该技术支持同时支持的，在单个组织部分上对多达42种抗体的空间保存定量。我们有一个现有的库在27种经过验证的肾脏和免疫抗体中，已经开发了一种机器学习方案来快速和准确地量化并定位使用IMC鉴定的人肾中的所有细胞。我们将首先增加经过验证的抗体面板，并优化我们的IMC协议以进行AIN （SA 1）。然后，我们将使用IMC在30 AIN中识别，量化和定位免疫和常驻电池响应耶鲁（发现队列）的病例和60个非AIN对照活检，其次是30例AIN病例和60个非AIN 来自JHU的控件（验证队列，SA 2）。最后，我们将定义细胞决定因素之间的关系 AIN和肾功能的恢复以及对类固醇的反应（SA3）。我们的发现不仅会导致 AIN中新型可药物靶标的鉴定，但也会改善AIN的临床组织学诊断。