DEK and TNF inhibitors in juvenile arthritis

DEK 和 TNF 抑制剂治疗幼年关节炎

• 批准号: 8311059
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311059
• 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)：幼年型特发性关节炎(JIA)是一种常见的儿童衰弱疾病，在分子水平上了解很少，通常缺乏指导临床治疗的有用生物标志物。JIA治疗的最新进展是开始抗肿瘤坏死因子治疗，并在临床上取得了很好的效果。然而，这些疗法非常昂贵，容易感染，而且对儿童的长期副作用尚不清楚。因此，JIA患儿何时停止抗肿瘤坏死因子治疗是一个重大问题。在辛辛那提儿童医院医学中心Daniel Lovell博士的指导下，五个中心正在开始一项临床试验，在仔细监测潜在生物标记物的情况下，当疾病保持不活动状态六个月时，将停止对患有多关节或延长少关节JIA的儿童进行抗肿瘤坏死因子治疗。随后将跟踪这些患者随后的临床和实验室过程。在这里，我们建议利用这一重要的临床试验来了解DEK蛋白在JIA的发病、恶化和治疗中的作用。由于目前还没有良好的血清学测试来监测JIA的治疗情况，重要的是，几个小组已经显示出JIA与针对生化上独特的DEK蛋白的自身抗体之间存在很强的相关性，DEK蛋白是一种经历重大翻译后修饰的蛋白质，包括磷酸化、乙酰化和多聚核糖化。我们现在已经开始了解自身抗体识别的DEK的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DEK通常是一种核蛋白，实际上可以由单核细胞分泌并由凋亡的T细胞释放，并对中性粒细胞、CD8+T细胞和自然杀伤细胞起趋化作用。由于已发现肿瘤坏死因子可以刺激DEK的表达，并且我们可以通过阻断肿瘤坏死因子抑制DEK的分泌，我们推测DEK和/或DEK抗体是预测哪些患者可以安全地停止抗肿瘤坏死因子治疗的潜在生物标志物。此外，我们认为DEK可能在JIA的自身免疫中发挥直接作用，并将在这项临床试验的背景下研究这一假说。我们建议评估在抗肿瘤坏死因子治疗期间和之后定期抽取患者血液中的DEK抗原和抗体的数量和性质，并检查这些参数是否随着肿瘤坏死因子的阻断而改变，或者允许我们确定是否可以使用DEK或DEK抗体来预测谁可以停止抗肿瘤坏死因子治疗。我们还将描述哪些翻译后修饰增强了DEK的自身抗原性，以及它作为炎症细胞趋化剂的能力。因此，拟议中的研究将使用一项重要的临床试验来解决DEK是否可以作为JIA的生物标记物，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JIA生物学的了解，并改善对这一非常重要的儿童疾病的管理。公共卫生相关性：青少年特发性关节炎(JIA)是一种常见的、使人虚弱的疾病，其发病机制尚不清楚，也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可能在JIA的发病机制中起重要作用，并可能作为一个有用的生物标志物。在一项将解决JIA患者何时适宜停止抗肿瘤坏死因子治疗的临床试验的背景下，我们建议研究DEK在JIA的发病和治疗中的作用。

项目成果

DEK expression in melanocytic lesions.

黑素细胞病变中的DEK表达。

• DOI: 10.1016/j.humpath.2010.10.022
• 发表时间: 2011-07
• 期刊: HUMAN PATHOLOGY
• 影响因子: 3.3
• 作者: Kappes, Ferdinand;Khodadoust, Michael S.;Yu, Limin;Kim, David S. L.;Fullen, Douglas R.;Markovitz, David M.;Ma, Linglei
• 通讯作者: Ma, Linglei