Immunologic Mechanisms of Progressive Glomerulosclerosis

进行性肾小球硬化症的免疫学机制

• 批准号: 9902420
• 负责人: Joshua M Thurman
• 金额: $ 34.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902420
• 关键词: Affect; Animal Model; Antibodies; Autoimmune Process; Binding; Cells; Chemicals; Chronic; Chronic Kidney Failure; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Inactivators; Complement Membrane Attack Complex; Complement component C4a; Data; Deposition; Development; Disease; Disease Pathway; Disease Progression; Endothelial Cells; Epitopes; Etiology; Fostering; Genetic; Human; Immune; Immunoglobulin M; Immunologics; In Vitro; Inflammatory; Injury; Injury to Kidney; Kidney; Kidney Diseases; Lead; Mediating; Metabolic; Modeling; Morbidity - disease rate; Mus; Pathogenesis; Patients; Pharmaceutical Preparations; Plasma; Population; Prevalence; Process; Public Health; Publishing; Renal function; Research; Site; Somatic Mutation; Testing; Therapeutic; Tissues; United States; Urine; Work; base; blood pressure regulation; cell injury; cell type; complement system; experimental study; falls; glomerular endothelium; glomerulosclerosis; hemodynamics; humoral immunity deficiency; immunomodulatory therapies; improved; in vivo; injured; ischemic injury; mortality; natural antibodies; neoantigens; novel; novel therapeutics; therapeutic target

Chronic kidney disease (CKD) affects more than 13% of the population, and its prevalence in the United States is increasing. Regardless of the underlying etiology, CKD tends to progress once renal function falls below 50%. Glomerulosclerosis is a hallmark of CKD of all etiologies, suggesting that diverse primary diseases engage common final pathways of disease progression. Unfortunately, there are currently no specific therapies for slowing the progression of CKD and glomerulosclerosis. Interestingly, it has been known for decades that IgM and C3 are deposited in the glomeruli of some patients with CKD, although the significance of these deposits has remained elusive. Recent work has revealed that natural IgM (i.e. IgM that has not undergone somatic mutation) binds to neoepitopes expressed on injured cells. The tissue-bound IgM activates the complement system, contributing to further injury. This discovery prompted us to reexamine the significance of glomerular IgM deposits in patients with CKD. We have found that IgM binds to specific epitopes expressed in the glomeruli of mice after chemical, inflammatory, and ischemic injury. The glomerular IgM triggers complement activation, causing further renal injury. Our preliminary data also demonstrates that complement activation fragments are elevated in the plasma of human patients with CKD. The overall hypothesis of the current proposal is that natural antibody IgM binds to neoepitopes expressed in the glomerulus after a wide range of insults, and bound IgM activates the complement cascade. Once this injurious immune process starts, it generates additional neoepitopes for natural IgM, perpetuating the renal injury even if the primary disease process ceases. To test this hypothesis, the following specific aims will be pursued. 1) Test whether natural IgM causes progressive glomerulosclerosis. In this aim we will test whether mice deficient in soluble IgM are protected from CKD progression in two animal models, and we will test the ability of specific monoclonal IgM antibodies to restore injury. 2) Investigate the mechanisms of complement-mediated glomerular injury. The hypothesis for this aim is that C3a and C5a are generated in the glomeruli of subjects with CKD and promote glomerulosclerosis. We will examine the effects of these complement activation fragments on the different glomerular cell types in vitro and in vivo. 3) Develop novel therapies for the treatment of progressive CKD. The hypothesis for this aim is that a novel complement inhibitor that specifically targets injury-associated glomerular epitopes will slow the progression of renal disease. The experiments in this proposal will advance our understanding of the pathogenesis of CKD and foster the development of improved immunomodulatory treatments for this disease.

慢性肾病 (CKD) 影响超过 13% 的人口，其患病率在 美国正在增加。无论潜在的病因如何，一旦肾病发生，CKD 往往会进展。 功能下降到50%以下。肾小球硬化是所有病因中 CKD 的一个标志，表明不同的病因 原发性疾病涉及疾病进展的共同最终途径。不幸的是，目前有 没有减缓 CKD 和肾小球硬化进展的具体疗法。有趣的是，已经 几十年来我们就知道 IgM 和 C3 沉积在一些 CKD 患者的肾小球中， 尽管这些矿床的重要性仍然难以捉摸。最近的工作表明，自然 IgM（即未经历体细胞突变的 IgM）与受损细胞上表达的新表位结合。 组织结合的 IgM 激活补体系统，导致进一步损伤。这一发现 促使我们重新审视 CKD 患者肾小球 IgM 沉积的意义。我们发现 IgM 与化学、炎症和化学反应后小鼠肾小球中表达的特定表位结合 缺血性损伤。肾小球 IgM 触发补体激活，导致进一步的肾损伤。我们的 初步数据还表明，补体激活片段在血浆中升高。 患有 CKD 的人类患者。当前提案的总体假设是天然抗体 IgM 结合 广泛的损伤后肾小球中表达的新表位，并且结合的 IgM 激活 补体级联。一旦这种有害的免疫过程开始，它就会产生额外的新表位 天然 IgM，即使原发疾病过程停止，也会使肾损伤持续存在。为了测试这个 假设，将追求以下具体目标。 1) 检测天然IgM是否引起进行性 肾小球硬化。为此，我们将测试缺乏可溶性 IgM 的小鼠是否能够免受 CKD 的影响 我们将在两种动物模型中测试特定单克隆 IgM 抗体的能力 恢复伤害。 2）研究补体介导的肾小球损伤的机制。假设 为此目的，C3a 和 C5a 在 CKD 受试者的肾小球中生成，并促进 肾小球硬化。我们将检查这些补体激活片段对不同 体外和体内的肾小球细胞类型。 3) 开发治疗进展性 CKD 的新疗法。 该目标的假设是一种新型补体抑制剂，专门针对损伤相关的 肾小球表位将减缓肾脏疾病的进展。本提案中的实验将 增进我们对 CKD 发病机制的了解，并促进改进的发展 针对这种疾病的免疫调节治疗。