TNF-like weak inducer of apoptosis (TWEAK) signaling: a novel therapeutic target

TNF 样弱凋亡诱导剂 (TWEAK) 信号传导：一种新的治疗靶点

• 批准号: 8183923
• 负责人: CHAIM PUTTERMAN
• 金额: $ 41.5万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8183923
• 关键词: Adrenal Cortex Hormones; Affect; Albuminuria; Antibodies; Antigen-Antibody Complex; Apoptosis Promoter; Basement membrane; Binding; CCL2 gene; CXCL10 gene; Cell Proliferation; Cells; Characteristics; Chemotaxis; Chronic; Clinical; Clinical Trials; Cytotoxic agent; Deposition; Development; Disease; Dose; End stage renal failure; Endothelial Cells; Epithelial Cells; Fibroblasts; Goals; Hematuria; Human; Immune Cell Activation; Immunosuppression; In Vitro; Inbred MRL lpr Mice; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Kidney; Kidney Diseases; Life; Ligands; Lupus; Lupus Nephritis; Macrophage Activation; Mediator of activation protein; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Nephritis; Pathogenesis; Pathway interactions; Patients; Play; Process; Protein Family; Proteinuria; RANTES; Regimen; Relative (related person); Role; Signal Transduction; Systemic Lupus Erythematosus; T-Lymphocyte; TNF gene; TNFRSF5 gene; TNFSF5 gene; Therapeutic; Treatment Protocols; Tumor Necrosis Factor Receptor; Vascular Cell Adhesion Molecule-1; base; cell type; chemokine; cytokine; glomerulosclerosis; in vivo; kidney cell; lupus prone mice; macrophage; member; mesangial cell; neglect; new therapeutic target; podocyte; receptor; urinary

DESCRIPTION (provided by applicant): While both infiltrating macrophages and glomerular cells are crucial in the pathogenesis of lupus nephritis (LN), one of the most common and dangerous clinical manifestations of SLE, their interactions remain incompletely understood. Appreciating the relative contribution of macrophages and resident kidney cells, and their interactions, would help us to understand the pathogenesis of LN and could provide an opportunity for more targeted therapies. Abnormal interaction of TNF-receptor superfamily members and their cognate ligands are believed to play a central role in lupus pathogenesis. Inhibition of several of these ligand/receptor pairs has already shown promise in clinical trials in human lupus. TWEAK is a secreted cytokine member of the TNF-ligand superfamily. TWEAK binds to its receptor, Fn14, and stimulates macrophages, fibroblasts, synoviocytes, and endothelial cells to secrete chemokines, cytokines, and other proinflammatory mediators. Our preliminary results suggest that TWEAK/Fn14 signaling is essential in the pathogenesis of LN: 1. Urinary TWEAK levels are increased in human LN, and correlate with disease activity; 2. The TWEAK receptor, Fn14, is expressed by murine and human mesangial cells (MC) and podocytes in vitro, and in lupus kidneys in vivo. Treatment of podocytes with TWEAK leads to increased expression of key pathogenic cytokines, including MCP-1, RANTES, VCAM-1, and IP-10. Increased MCP-1 in the kidney leads to recruitment of inflammatory cells and amplification of the local inflammatory process; 3. Injection of TWEAK to B6 mice increases MCP-1 expression, promotes chemotaxis of T cells and macrophages into the kidney, and stimulates glomerular cell proliferation; 4. Preliminary studies show a beneficial effect of anti-TWEAK antibodies in reducing proteinuria in the chronic graft versus host murine model of SLE. Our hypotheses are that blocking TWEAK-Fn14 signaling will be beneficial in treatment of murine LN, and that TWEAK activation of both macrophages and resident kidney cells is central in the contribution of this cytokine to inflammatory renal disease in lupus. Our Specific Aims for this proposal are as follows: I. Investigate the direct involvement of TWEAK-Fn14 signaling in the pathogenesis of LN and determine its therapeutic potential by a) characterizing lupus prone MRL-lpr/lpr (MRL-lpr) mice with Fn14 deficiency; and b) administering an anti- TWEAK monoclonal antibody (mAb) to lupus prone mice; II. Characterize the relative contribution of TWEAK activation in macrophages to the pathogenesis of LN; III. Determine the effect of TWEAK signaling in resident kidney cells, and particularly podocytes, in the development of LN, including albuminuria and glomerulosclerosis. PUBLIC HEALTH RELEVANCE: A cytokine member of the TNF family of proteins, has many pro-inflammatory effects on several different cell types including mouse and human kidney cells. Some of the inflammatory mediators induced by TWEAK are important in the inflammation observed in kidneys affected by lupus. Our goals for this proposal are to investigate the importance of TWEAK binding to its receptor on different cell types in lupus, and to explore whether an anti-TWEAK antibody may be helpful in treating kidney inflammation.

描述（由申请人提供）：虽然浸润性巨噬细胞和肾小球细胞在狼疮肾炎（LN）的发病机制中都是至关重要的，狼疮肾炎是SLE最常见和最危险的临床表现之一，但它们之间的相互作用尚不完全清楚。了解巨噬细胞和常驻肾细胞的相对作用及其相互作用，将有助于我们了解LN的发病机制，并为更有针对性的治疗提供机会。tnf -受体超家族成员及其同源配体的异常相互作用被认为在狼疮发病中起核心作用。这些配体/受体对的抑制已经在人类狼疮的临床试验中显示出希望。TWEAK是tnf配体超家族的分泌细胞因子成员。TWEAK与其受体Fn14结合，刺激巨噬细胞、成纤维细胞、滑膜细胞和内皮细胞分泌趋化因子、细胞因子和其他促炎介质。我们的初步结果表明，TWEAK/Fn14信号通路在LN的发病机制中起着至关重要的作用。尿中TWEAK水平在LN患者中升高，并与疾病活动相关；2. TWEAK受体Fn14在体外以及狼疮肾脏中由小鼠和人的系膜细胞（MC）和足细胞表达。用TWEAK处理足细胞导致关键致病细胞因子的表达增加，包括MCP-1、RANTES、VCAM-1和IP-10。肾脏MCP-1的升高导致炎症细胞的募集和局部炎症过程的放大；3. 注射TWEAK使B6小鼠MCP-1表达增加，促进T细胞和巨噬细胞趋化进入肾脏，刺激肾小球细胞增殖；4. 初步研究显示抗tweak抗体在SLE慢性移植物抗宿主小鼠模型中具有减少蛋白尿的有益作用。我们的假设是，阻断TWEAK- fn14信号传导将有利于治疗小鼠LN，并且巨噬细胞和常驻肾细胞的TWEAK激活是该细胞因子在狼疮炎症性肾脏疾病中的核心作用。我们的具体目标是：1 .通过表征Fn14缺乏的狼疮易感性MRL-lpr/lpr （MRL-lpr）小鼠，研究twist -Fn14信号在LN发病中的直接作用，并确定其治疗潜力；b)对狼疮易感小鼠给予抗TWEAK单克隆抗体（mAb）；2。表征巨噬细胞中TWEAK激活对LN发病机制的相对贡献；3。确定在包括蛋白尿和肾小球硬化在内的LN发展过程中，常驻肾细胞，特别是足细胞中TWEAK信号的作用。