DEK and TNF inhibitors in juvenile arthritis

DEK 和 TNF 抑制剂治疗幼年关节炎

基本信息

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
项目类别：
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

项目摘要

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）：少年特发性关节炎（JIA）是一种常见的，使人衰弱的童年疾病，在分子水平上对此非常了解，并且通常缺乏有用的生物标志物来指导临床管理。 JIA治疗的最新进展是抗TNF疗法的开始，该治疗在临床上非常有效。但是，这些疗法非常昂贵，并且易于感染，而且儿童的远距离副作用尚不清楚。因此，何时在JIA儿童中停止抗TNF治疗是一个主要问题。在辛辛那提儿童医院医疗中心的丹尼尔·洛维尔（Daniel Lovell）博士的指导下，五个中心开始进行临床试验，在仔细监测潜在的生物标志物的情况下，抗TNF疗法将在疾病持续六个月的情况下，疾病持续六个月，抗TNF疗法将在多关节或扩展的寡头jia中停止使用。然后将遵循这些患者的随后临床和实验室课程。在这里，我们建议利用这项重要的临床试验，以了解DEK蛋白在JIA的发病机理，加剧和管理中的作用。由于目前尚无良好的血清学检测来监测JIA的治疗，因此很重要的是，几个小组与生物化学上不同的DEK蛋白之间显示出很强的相关性，这种蛋白质是经过重大的翻译后修饰的蛋白质，包括磷酸化，乙酰化和多吡ry替素化。我们现在已经开始了解自身抗体所识别的dek后翻译后修改和域。我们还发现患者的血液和滑液中的DEK蛋白，并且已经观察到，DEK实际上可以由单核细胞分泌，并被凋亡T细胞释放，并用作中性粒细胞，CD8+ T细胞和天然杀伤剂细胞的化学吸引力。由于已经发现DEK表达受到TNF的刺激，并且我们可以通过TNF阻滞来抑制DEK分泌，因此我们假设DEK和/或DEK抗体的DEK和/或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，我们建议DEK可能在JIA的自身免疫中发挥直接作用，并将在该临床试验的背景下研究该假设。我们建议在抗TNF治疗期间和之后定期绘制的患者血液中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，还是允许我们确定DEK或DEK抗体是否可以用于预测谁可以从抗TNF治疗中取出谁。我们还将描绘哪些翻译后修饰增强了DEK的自身抗原性及其作为炎性细胞的化学吸引力的能力。因此，拟议的研究将使用重要的临床试验来解决DEK是否可以用作JIA的生物标志物，并了解DEK的免疫生物学。因此，这些研究有可能提高我们对JIA生物学的理解，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：少年特发性关节炎（JIA）是一种常见且令人衰弱的疾病，其发病机理已被研究且知识不足，并且缺乏为指导诊断和治疗决定的生物标志物。最近的发现表明，DEK蛋白和该蛋白的抗体在JIA的发病机理中可能很重要，并且可能是有用的生物标志物。在一项临床试验的背景下，该试验将解决何时在JIA患者中停止抗TNF治疗的关键问题，我们建议研究DEK在JIA的发病机理和管理中的作用。