A Systems Biology Approach for Pediatric and Adult Autoimmune Diseases

描述(由申请者提供)：我们建议创建一个卓越的自身免疫中心，将包括临床医生、人类免疫学家(基础和翻译)、在自身免疫方面具有临床专业知识和研究经验的内科科学家、生物信息学家和老年组学/系统生物学家的努力。总而言之，组建的团队在临床试验方面拥有广泛的背景，并在融合基础和临床科学方面拥有经过证明的记录。这个团队致力于将创新的治疗方法从实验室工作台带到患者的床边。在这种协作环境下，提出了一种系统生物学方法，以同时关注儿童和成人自身免疫性疾病。 该中心的目标是： 1)评估新的靶向治疗的有效性，2)使用最先进的基因组方法开发简单而强大的生物标记物，3)了解最近发现的T细胞亚群在疾病发病机制中的作用，以及4)评估儿童和成人自身免疫性疾病中的抗原特异性反应。 这些项目将更好地了解特定自身免疫性疾病的发病机制，并使我们能够开发一种策略，基于新的转录标记评估疾病活动，以及识别自身抗原特异性免疫反应。 该中心将提供： 1)针对牛皮癣和皮肌炎的特定细胞因子的创新临床试验。 2)皮肌炎、银屑病、狼疮和多发性硬化症的生物标志物的开发。 3)寻找治疗皮肌炎的新靶点。 4)开发检测自身抗原特异性免疫反应的方法。 5)开发独特的人类自身免疫性疾病微阵列数据库。 临床部分(库什，J) 临床成分描述(由申请人提供)：贝勒免疫研究所旨在召集一支杰出的临床研究团队，对特定的自身免疫性疾病进行尖端临床试验。这一独特的研究人员和临床医生团队在贝勒大学医学中心、德克萨斯大学西南医学中心、达拉斯的德克萨斯苏格兰礼仪医院和西北大学都有预约。这些人才来自皮肤科、风湿科、神经科、儿科和人类免疫学等不同专业的不同项目。它们为临床试验提供了一套无与伦比的资源，并在融合基础科学和临床科学方面拥有经过证明的记录。事实上，这个团队致力于将创新的治疗方法从实验室工作台带到患者的床边。有了这样优秀的合作参与者，这里提出了一种系统生物学的方法，研究儿童和成人的自身免疫性疾病。为此，提出了两个第二阶段随机、双盲、安慰剂阶段对照临床试验。第一个试验调查用阿纳金纳阻断IL-1是否会对青少年皮肌炎患者带来客观的疾病改善。试验设计将证明：1)在研究早期接受Anakinra治疗的患者是否比后来接受治疗的患者改善时间更早；以及2)在失明阶段的第8周，早期治疗组的患者改善的比例是否会明显更大。机制研究将利用基因表达谱分析来寻找一种新的JDM诊断测试，以及跟踪和预测患者对治疗的反应的疾病活动指标和生物标记物。第二个临床项目建议将α-IL-17用于斑块型牛皮癣和牛皮癣关节炎患者。具体地说，这项研究将评估a-IL-17在这些患者中的安全性和有效性，并确定达到PASI 75或ACR20终点的时间以及这种反应在24周内的可持续性。相关研究将建立血液转录标记物来预测接受a-IL-17治疗的患者的临床反应，确定转录评分是否可以用来评估疾病的活动性，并分析IL-17阻断对B和T细胞亚群的影响(S)。 在北卡罗来纳大学组建一个充满活力的临床研究团队，对自身免疫性疾病进行最先进的临床试验，将具有重要价值，并加快将研究从实验室平台带到床边的进程。该团队提出了两项重要的试验，将评估a-IL-1对青少年皮肌炎的治疗和IL-17对牛皮癣疾病的阻断。

DESCRIPTION (provided by applicant): We propose to create an Autoimmunity Center of Excellence that will incorporate the efforts of clinicians, human immunologists (both basic and translational), physician-scientists with clinical expertise and research experience in autoimmunity, bioinformaticians, and geriomics/systems biologists. Together, the assembled group has an extensive background in clinical trials and a proven track record for merging basic and clinical science. This team is committed to bringing innovative treatments from the laboratory bench to their patients' bedside. Within this collaborative setting, a systems biology approach is proposed to focus on both pediatric and adult autoimmune diseases. The goals of the Center are: 1) To assess the efficacy of novel targeted therapies, 2) To develop simple and robust biomarkers using state-of-the-art genomic approaches, 3) To understand the role of recently identified T cell subsets in disease pathogenesis, and 4) To assess antigen-specific responses in pediatric and adult autoimmune diseases. These projects will provide a better understanding of the pathogenesis of specific autoimmune diseases and allow us to develop a strategy to assess disease activity based on novel transcriptional markers as well as to identify autoantigen-specific immune responses. The Center will deliver: 1) Innovative clinical trials targeting specific cytokines in psoriasis & dermatomyositis. 2) Development of biomarkers for dermatomyositis, psoriasis, lupus and multiple sclerosis. 3) Identification of novel therapeutic targets in dermatomyositis. 4) Development of assays to test autoantigen-specific immune responses. 5) Development of a unique microarray database of human autoimmune diseases. CLINICAL COMPONENT (Cush, J) CLINICAL COMPONENT DESCRIPTION (provided by applicant): Baylor Institute for Immunology Research aims to bring together a distinguished team of clinical investigators to conduct cutting-edge clinical trials on specific autoimmune diseases. This unique group of investigators and clinicians has appointments at Baylor University Medical Center, UT Southwestern Medical Center, Texas Scottish Rite Hospital in Dallas and Northwestern University. These talented individuals have been enlisted from diverse programs with subspecialties in dermatology, rheumatology, neurology, pediatrics, and human immunology. They provide a set of inimitable resources for clinical trials and have a proven track record for merging basic and clinical science. Indeed, this team is committed to bringing innovative treatments from the laboratory bench to their patients' bedside. With such outstanding collaborative players, a systems biology approach is proposed here which investigates both pediatric and adult autoimmune disease. To this end, two Phase II randomized, double-blind, placebo-phase controlled clinical trials are proposed. The first trial investigates whether blocking IL-1 with Anakinra will result in objective disease improvement for patients with Juvenile Dermatomysitis. The trial design will demonstrate: 1) if the time to improvement for patients receiving Anakinra early in the study will be earlier than those who receive later treatment; and 2) if the proportion of patients improved at week 8 of the blinded phase will be significantly greater in the early treatment group. Mechanistic studies will utilize gene expression profiling assays to find a novel diagnostic test for JDM as well as disease activity measures and biomarkers to follow and predict patients' response to therapy. The second clinical project proposes to use a-IL-17 in patients with plaque psoriasis as well as psoriatic arthritis. Specifically, this study will assess the safety and efficacy of a-IL-17 in these patients and determine both the time to achieve endpoints of a PASI 75 or ACR20 and sustainability of such responses at 24 weeks. Associated studies will establish blood transcriptional markers to predict clinical responses in patients treated with a-IL-17, determine if transcriptional scores can be used to assess disease activity, and analyze the effect(s) of IL-17 blockade on B and T cell subsets. A dynamic team of clinical investigators assembled at BUR to conduct state-of-the-art clinical trials on autoimmune disease would be of great value and accelerate the process of bringing research from the laboratory bench to the bedside. This team proposes two important trials that will assess a-IL-1 treatment in Juvenile Dermatomyositis and IL-17 blockade in psoriatic diseases.