DEK and TNF inhibitors in juvenile arthritis

DEK 和 TNF 抑制剂治疗幼年关节炎

• 批准号: 8130630
• 负责人: David Michael Markovitz
• 金额: $ 37.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8130630
• 关键词: Acetylation; Acute Myelocytic Leukemia; Address; Adverse effects; Ancillary Study; Anti-Inflammatory Agents; Anti-Tumor Necrosis Factor Therapy; Antibodies; Antigens; Antinuclear Antibodies; Apoptotic; Autoantibodies; Autoimmune Diseases; Autoimmunity; Biological Markers; Biology; Blood; Blood specimen; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chemotactic Factors; Child; Childhood; Chromatin; Chronic Childhood Arthritis; Clinic; Clinical; Clinical Management; Clinical Trials; Cyclosporins; DNA Repair; DNA biosynthesis; Dexamethasone; Diagnostic; Disease; Funding; Gene Expression Regulation; Hospitals; Human; Immunobiology; In Vitro; Infection; Inflammatory; Investigation; Joints; Laboratories; Long-Term Effects; Malignant Neoplasms; Medical; Medical center; Messenger RNA; Migration Assay; Molecular; Monitor; Natural Killer Cells; Nature; Nuclear; Nuclear Antigens; Nuclear Protein; Oncogenes; Opportunistic Infections; Pathogenesis; Patients; Pediatric Hospitals; Phosphoproteins; Phosphorylation; Play; Post-Translational Protein Processing; Process; Proteins; Recruitment Activity; Recurrence; Relapse; Research Personnel; Rheumatism; Role; Serologic tests; Structure; Synovial Fluid; T-Lymphocyte; TNF gene; Therapeutic; United States National Institutes of Health; autoimmune arthritis; design; disability; extracellular; human Dek protein; improved; in vivo; inhibitor/antagonist; macrophage; monocyte; neutrophil; public health relevance; response

DESCRIPTION (provided by applicant): Juvenile Idiopathic Arthritis (JIA) is a common, debilitating disease of childhood that is very poorly understood at the molecular level, and for which useful biomarkers to guide clinical management are generally lacking. A recent advance in the therapy of JIA has been the initiation of anti-TNF therapy, which has been clinically quite efficacious. However, these therapies are very expensive and predispose to infections, and the long-range side effects in children are not yet clear. Therefore, when to stop anti-TNF therapy in children with JIA is a major question. Five centers, under the direction of Dr. Daniel Lovell at the Cincinnati Children's Hospital Medical Center, are commencing a clinical trial in which, with careful monitoring of potential biomarkers, anti-TNF therapy will be discontinued in children with polyarticular or extended oligoarticular JIA when disease has remained inactive for six months. The subsequent clinical and laboratory course of these patients will then be followed. Here we propose to exploit this important clinical trial to understand the role of the DEK protein in the pathogenesis, exacerbation, and management of JIA. As good serological tests are currently not available to monitor treatment in JIA, it is significant that several groups have shown a strong correlation between JIA and auto-antibodies to the biochemically distinct DEK protein, a protein that undergoes significant post-translational modifications including phosphorylation, acetylation, and polyribosylation. We have now begun to understand the post-translational modifications and domains of DEK that the autoantibodies recognize. We also find DEK protein in the blood and synovial fluids of patients, and have made the observation that DEK, which is normally a nuclear protein, can actually be secreted by monocytic cells and released by apoptotic T cells, and serve as a chemoattractant for neutrophils, CD8+ T cells, and natural killer cells. As DEK expression has been found to be stimulated by TNF, and we can inhibit DEK secretion with TNF blockade, we hypothesize that DEK and/or antibodies to DEK are potential biomarkers for predicting which patients can safely stop anti-TNF therapy. In addition, we suggest that DEK may play a direct role in the autoimmunity of JIA, and will study that hypothesis in the context of this clinical trial. We propose to assess the quantity and nature of DEK antigen and antibody in the blood of patients drawn at regular intervals during and after anti-TNF therapy, and to examine whether these parameters change with TNF blockade or allow us to ascertain whether DEK or DEK antibodies can be used to predict who can be taken off of anti-TNF therapy. We will also delineate which post-translational modifications enhance the autoantigenicity of DEK and its ability to function as a chemoattractant for inflammatory cells. Thus, the proposed studies will use an important clinical trial to address whether DEK can be used as a biomarker in JIA, as well as to understand the immunobiology of DEK. These studies therefore have the potential to increase our understanding of the biology of JIA and to improve management of this very important disease of children. Public Health Relevance: Juvenile Idiopathic Arthritis (JIA) is a common and debilitating disease, the pathogenesis of which is understudied and poorly understood, and for which biomarkers to guide diagnostic and therapeutic decisions are lacking. Recent findings suggest that the DEK protein, and antibodies to this protein, may be important in the pathogenesis of JIA, and might serve as a useful biomarker. Within the context of a clinical trial that will address the key issue of when it is appropriate to discontinue anti-TNF therapy in patients with JIA, we propose to study the role of DEK in the pathogenesis and management of JIA.

描述（由申请人提供）：幼年特发性关节炎（JIA）是一种常见的、使人衰弱的儿童疾病，在分子水平上对其了解甚少，并且通常缺乏指导临床治疗的有用生物标志物。 JIA 治疗的最新进展是抗 TNF 疗法的启动，该疗法在临床上相当有效。然而，这些疗法非常昂贵，并且容易引起感染，而且对儿童的长期副作用尚不清楚。因此，何时停止JIA儿童的抗TNF治疗是一个主要问题。在辛辛那提儿童医院医疗中心 Daniel Lovell 博士的指导下，五个中心正在开始一项临床试验，在仔细监测潜在的生物标志物的情况下，对于患有多关节或扩展性少关节 JIA 的儿童，将停止抗 TNF 治疗。疾病已持续六个月不活跃。然后将跟踪这些患者随后的临床和实验室过程。在这里，我们建议利用这项重要的临床试验来了解 DEK 蛋白在 JIA 发病机制、恶化和治疗中的作用。由于目前尚无良好的血清学测试来监测 JIA 的治疗，因此重要的是，几个研究小组已显示 JIA 与生化上不同的 DEK 蛋白的自身抗体之间存在很强的相关性，DEK 蛋白是一种经历显着翻译后修饰的蛋白，包括磷酸化、乙酰化和多核糖基化。我们现在已经开始了解自身抗体识别的 DEK 翻译后修饰和结构域。我们还在患者的血液和滑液中发现了DEK蛋白，并观察到通常为核蛋白的DEK实际上可以由单核细胞分泌并由凋亡T细胞释放，并作为中性粒细胞的趋化剂、CD8+ T 细胞和自然杀伤细胞。由于已发现 DEK 表达受 TNF 刺激，并且我们可以通过 TNF 阻断来抑制 DEK 分泌，因此我们假设 DEK 和/或 DEK 抗体是预测哪些患者可以安全停止抗 TNF 治疗的潜在生物标志物。此外，我们认为 DEK 可能在 JIA 自身免疫中发挥直接作用，并将在本临床试验的背景下研究该假设。我们建议评估抗 TNF 治疗期间和治疗后定期抽取患者血液中 DEK 抗原和抗体的数量和性质，并检查这些参数是否随 TNF 阻断而变化，或者使我们能够确定 DEK 或 DEK 抗体是否存在可用于预测谁可以停止抗 TNF 治疗。我们还将描述哪些翻译后修饰增强了 DEK 的自身抗原性及其作为炎症细胞趋化剂的能力。因此，拟议的研究将利用一项重要的临床试验来解决 DEK 是否可以用作 JIA 的生物标志物，以及了解 DEK 的免疫生物学。因此，这些研究有可能增加我们对幼年特发性关节炎生物学的了解，并改善对这种非常重要的儿童疾病的管理。公共卫生相关性：幼年特发性关节炎 (JIA) 是一种常见且使人衰弱的疾病，其发病机制尚未得到充分研究和了解，而且缺乏指导诊断和治疗决策的生物标志物。最近的研究结果表明，DEK 蛋白和该蛋白的抗体在 JIA 的发病机制中可能很重要，并且可能作为有用的生物标志物。在一项临床试验的背景下，该临床试验将解决 JIA 患者何时适合停止抗 TNF 治疗的关键问题，我们建议研究 DEK 在 JIA 发病机制和治疗中的作用。