Immunomodulation in Multiple Sclerosis by Interferon B

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，其特征是髓磷脂丢失、神经胶质瘤、不同程度的轴突病理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，降低脑MRI活动，并减缓残疾的进展。然而，这种治疗的效果是局部的，并且大量的患者没有反应。该提案的总体目标是表征MS对IFN治疗反应的机制。A临床核心已经建立并维护了一个使用IFN治疗的复发缓解型MS患者的数据集。Core按顺序收集了研究参与者的血液，并存储了基因组DNA、总RNA、外周血淋巴细胞（PBMC）和血清，用于本应用程序中提出的研究。严格和完善的主要和次要临床终点可用于研究候选免疫（特异性目标1，分包合同B），分子（特异性目标2）和遗传（特异性目标3）替代标记物与临床治疗反应之间的有希望的关系。

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.