Role of IgM and Complement Activation in Glomerular Disease

IgM 和补体激活在肾小球疾病中的作用

• 批准号: 8394713
• 负责人: Sarah E Panzer
• 金额: $ 6.04万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394713
• 关键词: Address; Adrenal Cortex Hormones; Affinity; Albuminuria; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen Targeting; Area; Attenuated; B-Lymphocytes; Binding; Calcineurin inhibitor; Chronic Kidney Failure; Clinical; Clinical Markers; Clinical Treatment; Complement; Complement Activation; Complement Factor H; Data; Deposition; Diabetic Nephropathy; Dialysis procedure; Disease; Disease model; End stage renal failure; Epitopes; Exposure to; Extracellular Matrix; Focal Segmental Glomerulosclerosis; Histology; Immune; Immune system; Immunoglobulin M; Immunoglobulins; Immunosuppression; Immunosuppressive Agents; Injury; Injury to Kidney; Investigation; Kidney; Kidney Diseases; Kidney Failure; Knockout Mice; MS4A1 gene; Mediating; Mesangial Proliferative Glomerulonephritis; Mus; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Process; Public Health; Reducing Agents; Regulation; Renal Tissue; Renal glomerular disease; Research; Research Training; Role; Site; Therapeutic; Therapeutic Agents; Urea; Work; base; genetic regulatory protein; mesangial cell; mouse model; novel; podocyte; prevent; tositumomab

DESCRIPTION (provided by applicant): One of the prominent causes of chronic kidney disease (CKD) is due to glomerular disease. CKD often progresses to end stage renal disease and need for dialysis. The overall mechanism of glomerular disease is not well understood. However, one commonality seen in a variety of glomerular disease is deposition of IgM and the complement protein C3 within the glomerulus. Many clinicians believe the presence of IgM and C3 is not a causal factor in the disease process. However, we have evidence that IgM and C3 may play an active role in glomerular disease. This observation also raises the possibility of glomerular disease progressing through a common pathway involving IgM and C3. This project involves the use of a disease model to address this question. Specifically, we will use a mouse model to investigate if IgM and complement protein C3 cause glomerular disease. This is an important area of investigation because it provides a novel mechanism for glomerular disease and has the potential to completely alter our current clinical treatment of glomerular disease in patients. Specific aim 1 will address if IgM is a trigger of complement mediated progressive glomerular disease. We have demonstrated complement protein C3 deposition in mice deficient in the complement regulatory protein, factor H (factor H knockout mice). We have a colony of these same mice that also lack the ability to make B cells and therefore have no endogenous IgM. Our preliminary data show the novel finding that the glomerular C3 deposition seen in factor H knockout mice is attenuated when the mice are deficient in B cells. Specific aim 2 will investigate if anti-B cell therapeutic agents block complement activation within the glomerulus and prevent glomerular disease. We will administer an anti-B cell agent, anti-CD20 antibody, to determine its effect in our disease model. Anti-CD20 is an attractive therapeutic agent because it is commercially available for clinical use. We anticipate that administering anti-CD20 will bloc complement mediated glomerular disease. PUBLIC HEALTH RELEVANCE: Chronic kidney disease is a growing public health burden, which often leads to kidney failure and need for dialysis. Currently there are few therapeutic options available to patients to prevent progression of kidney disease. This research seeks to unravel the disease process between the immune system and the kidney and investigates the role for novel anti-inflammatory therapeutics in kidney disease.

描述（由申请人提供）：慢性肾病（CKD）的主要原因之一是肾小球疾病。 CKD 经常进展为终末期肾病并需要透析。肾小球疾病的总体机制尚不清楚。然而，多种肾小球疾病的一个共同点是 IgM 和补体蛋白 C3 在肾小球内沉积。许多临床医生认为 IgM 和 C3 的存在并不是疾病过程的致病因素。然而，我们有证据表明 IgM 和 C3 可能在肾小球疾病中发挥积极作用。这一观察结果还提出了肾小球疾病通过涉及 IgM 和 C3 的共同途径进展的可能性。该项目涉及使用疾病模型来解决这个问题。具体来说，我们将使用小鼠模型来研究 IgM 和补体蛋白 C3 是否会导致肾小球疾病。这是一个重要的研究领域，因为它为肾小球疾病提供了一种新的机制，并有可能彻底改变我们目前对患者肾小球疾病的临床治疗。具体目标 1 将解决 IgM 是否是补体介导的进行性肾小球疾病的触发因素。我们已经证明补体蛋白 C3 在缺乏补体调节蛋白 H 因子的小鼠（H 因子敲除小鼠）中沉积。我们有一群同样的小鼠，它们也缺乏产生 B 细胞的能力，因此没有内源性 IgM。我们的初步数据表明，当小鼠缺乏 B 细胞时，H 因子敲除小鼠中的肾小球 C3 沉积会减弱。具体目标 2 将研究抗 B 细胞治疗药物是否能阻断肾小球内的补体激活并预防肾小球疾病。我们将施用抗 B 细胞制剂、抗 CD20 抗体，以确定其在我们的疾病模型中的效果。抗CD20是一种有吸引力的治疗剂，因为它可以商业化用于临床。我们预计施用抗 CD20 将阻止补体介导的肾小球疾病。 公众健康相关性：慢性肾病是日益严重的公众健康负担，通常会导致肾衰竭和需要透析。目前，患者可用于预防肾脏疾病进展的治疗选择很少。这项研究旨在揭示免疫系统和肾脏之间的疾病过程，并研究新型抗炎疗法在肾脏疾病中的作用。