Immunomodulation in Multiple Sclerosis by Interferon B

描述(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，以髓鞘丢失、胶质增生、不同程度的轴突病理和进行性神经功能障碍为特征。干扰素已被证明可以减少临床复发，减少脑部核磁共振活动，减缓残疾的进展。然而，这种治疗的效果是部分的，很大一部分患者没有反应。这项建议的总体目标是描述多发性硬化症患者对干扰素治疗的反应所涉及的机制。临床核心公司已经建立并维护了使用干扰素治疗的复发缓解期多发性硬化症患者的数据集。Core从研究参与者那里连续采集血液，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。严格和完善的初级和次级临床终点可用于研究候选免疫学(特异性目标1，分包合同B)、分子(特异性目标2)和遗传学(特异性目标3)替代标记与临床治疗反应之间的有希望的关系。 基于干扰素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，以阐明基本的治疗机制，并确定从这种治疗模式中受益最大的患者。具体目标1主要涉及治疗后激活的细胞标志物的表达。在特定目标2中，动态(实时)-聚合酶链式反应将用于分析干扰素治疗患者外周血单核细胞的转录图谱。最后，特殊目标3是潜在的基因-免疫治疗相互作用的药物基因组学研究。 在这项建议中，我们设计并提出了一个综合的多分析策略，以产生可靠的工作模型，以了解干扰素在自身免疫脱髓鞘过程中的生理机制。除了对干扰素基本生物学的新见解外，我们的结果还可能确定活性的替代标记物，并定义干扰素反应异质性的分子基础。

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.