Immunomodulation in Multiple Sclerosis by Interferon B

描述（由申请人提供）：多发性硬化（MS）是一种常见的CNS炎性疾病，其特征为髓鞘丢失、神经胶质增生、不同程度的轴突病变和进行性神经功能障碍。干扰素β（IFN？）已被证明可以减少临床复发，减少大脑MRI活动，并减缓残疾的进展。然而，这种治疗的效果是部分的，大量的患者没有反应。该提案的总体目标是表征MS中对IFN治疗的反应所涉及的机制。临床核心已经建立并维护了用IFN治疗的复发缓解型MS患者的数据集。Core已连续采集研究参与者的血液，并储存基因组DNA、总RNA、外周血淋巴细胞（PBMC）和血清，用于本申请中拟定的研究。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（特异性目的1，β B）、分子学（特异性目的2）和遗传学（特异性目的3）替代标志物与治疗临床应答之间的有希望的关系。 基于IFN是一种多效性免疫调节剂的假设，设计了一种多分析纵向策略来阐明基本的治疗机制，并确定将从这种治疗模式中获益最多的患者。具体目标1主要涉及治疗后细胞活化标志物的表达。在特定目标2中，将使用动力学（真实的时间）-PCR分析IFN？治疗患者PBMC中的转录谱。最后，具体目标3是潜在基因-免疫治疗相互作用的药物基因组学研究。 一个全面的多分析策略的设计，并提出了在这个建议，以产生可靠的工作模型，为了解的生理机制IFN？管理自身免疫性脱髓鞘。除了对干扰素的基本生物学有新的认识外，我们的研究结果还将潜在地确定活性的替代标记物，并确定干扰素应答异质性的分子基础。

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.