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) 是由药物暴露、感染或自身免疫性疾病引起的高达 20% 接受肾活检的患者会出现急性肾损伤 (AKI)。尽管我们目前有 2 种临床干预措施可用于治疗 AIN 患者（停用违规药物并皮质类固醇），40-60% 的 AIN 患者会继续发展为慢性肾病 (CKD)，即使得到适当的治疗。 AIN 中的肾脏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脏损伤。最近多种自身免疫性疾病和癌症的免疫基础恶化导致与相比，靶向疗法的开发表现出更高的疗效和更低的毒性皮质类固醇。因此，对免疫浸润和由此产生的驻留细胞（管状和血管）进行分析提供对引发和传播 AIN 的特定免疫事件的致病性理解的反应应导致更有效解决 AIN 的靶向治疗的开发和/或重新利用并防止进展为 CKD，并且潜在的毒性较小。来自多个研究组（包括我们自己的研究组）的数据表明，CD4+ T 辅助细胞（特别是 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 以及一些类型的细胞 2 AIN患者尿液或肾脏中的免疫力、肥大细胞和嗜酸性粒细胞含量较高。基于这些根据数据，我们假设肾脏中的 TH2/TH9 T 辅助细胞本身在促进 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个假设 AIN 患者的肾脏免疫浸润以及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，经 3 名肾脏病理学家判定显示 AIN 中心（耶鲁大学和约翰霍普金斯大学）作为本研究的发现和验证队列。执行定量分析时，我们将使用一种称为成像质量细胞术 (IMC) 的成像技术，该技术支持同步、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，可以快速、准确地准确量化和定位使用 IMC 识别的人类肾脏中的所有细胞。我们将首先增加经过验证的抗体组并优化我们的 IMC 方案以用于 AIN 研究（SA 1）。然后，我们将使用 IMC 来识别、量化和定位 30 AIN 中的免疫和驻留细胞反应耶鲁大学（发现队列）的 60 例非 AIN 对照活检，随后是 30 例 AIN 病例和 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素之间的关系 AIN 和肾功能恢复以及对类固醇的反应 (SA3)。我们的发现不仅会导致识别 AIN 中新的药物靶点，也能改善 AIN 的临床组织学诊断。