Immunomodulation in Multiple Sclerosis by Interferon B

干扰素 B 对多发性硬化症的免疫调节

• 批准号: 6927050
• 负责人: Jorge R. Oksenberg
• 金额: $ 31.03万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927050
• 关键词: biomarker; clinical research; gene expression; genetic markers; genetic polymorphism; human subject; immunogenetics; immunomodulators; immunoregulation; immunotherapy; interferon beta; lymphocyte; mathematical model; molecular biology information system; multiple sclerosis; myelinopathy; polymerase chain reaction

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a common inflammatory disorder of the CNS characterized by myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. Interferon beta (IFN¿) has been shown to decrease clinical relapses, reduce brain MRI activity, and slow progression of disability. However, the effect of this treatment is partial, and a significant amount of patients are not responders. The overall goal of this proposal is to characterize the mechanisms involved in the response to IFN¿ therapy in MS. A Clinical Core has established and maintains a dataset of patients with relapsing remitting MS treated with IFN¿. The Core has sequentially collected blood from study participants and store genomic DNA, total RNA, peripheral blood lymphocytes (PBMC) and sera for the studies proposed in this application. Stringent and well established primary and secondary clinical endpoints are available to investigate promising relationships between candidate immunological (specific aim 1, subcontract B), molecular (specific aim 2) and genetic (specific aim 3) surrogate markers and the clinical response to treatment. Based on the hypothesis that IFN¿ is a pleiotropic immunoregulatory reagent, a multi-analytical longitudinal strategy was designed to elucidate basic therapeutic mechanisms and identify the patients who will benefit the most from this mode of therapy. Specific Aim 1 is primarily concerned with the expression of cellular markers of activation following treatment. In Specific Aim 2, kinetic (real time)-PCR will be used to analyze transcriptional profiles in PBMC of IFN¿ treated patients. Finally, Specific Aim 3 is a pharmacogenomic study of potential gene-immunotherapy interactions. A comprehensive multi-analytical strategy was designed and is presented in this proposal to generate reliable working models for the understanding of the physiological mechanisms of IFN¿ administration in autoimmune demyelination. In addition to new insights into the fundamental biology of interferons, our results will potentially identify surrogate markers of activity, and define the molecular basis of interferon response heterogeneity.

描述（由申请人提供）：多发性硬化症（MS）是一种常见的中枢神经系统炎症性疾病，其特征为髓磷脂缺失、神经胶质增生、不同程度的轴突病理学和进行性神经功能障碍。 β 干扰素 (IFN¿) 已被证明可以减少临床复发、减少脑部 MRI 活动并减缓残疾进展。然而，这种治疗的效果是部分的，并且大量患者没有反应。该提案的总体目标是描述多发性硬化症中干扰素治疗的反应机制。临床核心已建立并维护接受 IFN¿ 治疗的复发缓解型多发性硬化症患者的数据集。 Core 已依次收集研究参与者的血液并存储基因组 DNA、总 RNA、外周血淋巴细胞 (PBMC) 和血清，用于本申请中提出的研究。严格且完善的主要和次要临床终点可用于研究候选免疫学（具体目标 1，分包 B）、分子（具体目标 2）和遗传（具体目标 3）替代标志物与临床治疗反应之间的有希望的关系。 基于 IFN 是一种多效性免疫调节试剂的假设，设计了一种多分析纵向策略来阐明基本治疗机制并确定将从这种治疗模式中受益最多的患者。具体目标 1 主要涉及治疗后细胞激活标记物的表达。在具体目标 2 中，动态（实时）-PCR 将用于分析 IFN 治疗患者的 PBMC 转录谱。最后，具体目标 3 是潜在基因-免疫疗法相互作用的药物基因组学研究。 本提案设计并提出了一种全面的多分析策略，以生成可靠的工作模型，以了解自身免疫性脱髓鞘中 IFN 给药的生理机制。除了对干扰素基础生物学的新见解外，我们的结果还将有可能识别活性的替代标记，并定义干扰素反应异质性的分子基础。