INTERFERON-B AND COPOLYMER-I IN MULTIPLE SCLEROSIS.

申请人是马里兰大学神经病学副教授，巴尔的摩VA医学中心的神经病学专家。目前的学术活动包括多发性硬化症（MS）的临床和基础研究。目前，申请人的实验室有两个正在进行的研究项目：第一个是VA资助的优异评审奖，到2002年3月，研究病毒在人类神经元中的持久性机制；第二个是研究两种新批准的药物，IFNbeta和共聚物-1的治疗机制。在过去的6年中，有4名博士后在申请人的实验室进行了与MS相关的研究。环境：马里兰多发性硬化症中心是国际公认的多发性硬化症临床和基础研究中心，该中心的临床研究有助于FDA批准目前上市的3种多发性硬化症药物中的2种，即Betaseron和共聚物-1。每年有超过800名患者就诊，该中心参与了几项多地点临床试验。中心有5名全职MS专家，3名护士，2名辅助人员。研究：拟进行的研究将重点了解Betaseron和共聚物-1在ms Supplies中的治疗机制，目前该研究的部分技术支持由Betaseron和共聚物-1的制造商Berlex和TEVA分别提供。我们的具体目标包括：1。IL-12是一种与ms发病机制有关的促炎细胞因子，初步数据表明IFNbeta对外周血单核细胞（PBMNC）中IL-12具有细胞特异性调节作用。我们将在体外和离体研究这种调节作用的机制，使用来自MS患者的IFNbeta治疗前后的PBMNC。这些发现也将与MRI疾病活动相关联。2. 共聚物-1治疗多发性硬化症的机制我们将研究共聚物-1在接受该药物治疗的多发性硬化症患者体内获得的PBMNC中的免疫作用。这包括共聚物-1特异性调节细胞的诱导，这些细胞是否与髓磷脂抗原交叉反应并诱导细胞因子偏差，或者共聚物-1是否产生t细胞能量。这项研究可以帮助确定MS中与治疗反应相关的免疫网络的组成部分，从而有助于设计更有效的未来治疗方法。

Candidate: The applicant is an associate professor of Neurology at the university of Maryland and a staff neurologist at the Baltimore VA Medical Center. Current academic activities include clinical and basic research in multiple sclerosis (MS). Currently, there are two ongoing research projects in the applicant's laboratory: The first is a VA funded Merit Review Award through March, 2002 to examine mechanisms of virus persistence in human neurons, and the second is to examine the therapeutic mechanisms of 2 newly approved drugs for MS, IFNbeta and copolymer-1. During the past 6-years four postdoctoral fellows conducted research related to MS in the applicant's laboratory. Environment: The Maryland Center for MS is internationally recognized for clinical and basic research in MS. Clinical research at this center contributed to the FDA approval of 2 of the 3 currently marketed drugs for MS namely Betaseron and copolymer-1. More than 800 annual patient visits occur, and the center participates in several multisite clinical trials. The center is staffed by 5 full time MS specialists, 3 nurses, and 2 support staff. Research: The proposed research will focus on understanding the therapeutic mechanisms of Betaseron and copolymer-1 in MS. Supplies and partial technical support for this research is currently provided by Berlex and TEVA, the manufacturers of Betaseron and copolymer-1 respectively. Our specific aims include: 1. Examination of the modulatory effect of IFNbeta treatment on IL-12 in MS. IL-12 is a pro-inflammatory cytokine implicated in the pathogenesis of MS. Preliminary data indicate that IFNbeta has a cell-specific regulatory effect on IL-12 in peripheral blood mononuclear cells (PBMNC). We will examine the mechanism of this regulatory effect both in vitro and ex-vivo using PBMNC from MS patients pre- and post-treatment with IFNbeta. The findings will also be correlated with MRI disease activity. 2. Mechanisms of Copolymer-I therapy in MS. We will examine the immunologic effects of copolymer-1 in PBMNC obtained ex-vivo from MS patients treated with this drug. This includes induction of copolymer-1 specific regulatory cells, whether these cells cross react with myelin antigens and induce cytokine deviation, or whether copolymer-1 produces T-cell anergy. The proposed research could help identify components of the immunologic network in MS that are associated with response to treatment, and therefore help in the design of more effective future therapies.