INTERFERON-B AND COPOLYMER-I IN MULTIPLE SCLEROSIS.

候选人：申请人是马里兰州大学神经病学副教授和巴尔的摩退伍军人医疗中心的神经科医生。 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，在申请人的实验室中有两个正在进行的研究项目：第一个是VA资助的Merit Review Award，直到2002年3月，以检查病毒在人类神经元中持续存在的机制，第二个是检查两种新批准的MS药物IFN β和共聚物-1的治疗机制。 在过去的6年中，四名博士后研究员在申请人的实验室进行了与MS相关的研究。工作环境：马里兰州MS中心在MS的临床和基础研究方面得到国际认可。该中心的临床研究促成了FDA批准3种目前上市的MS药物中的2种，即倍他赛隆和共聚物-1。 每年有800多名患者就诊，该中心参与了多项多中心临床试验。 该中心由5名全职MS专家，3名护士和2名支持人员组成。调研：拟议的研究将侧重于了解Betaseron和共聚物-1在MS中的治疗机制。目前，Betaseron和共聚物-1的制造商Berlex和TEVA分别为这项研究提供了供应和部分技术支持。 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，IFN β对外周血单核细胞（PBMNC）中的IL-12具有细胞特异性调节作用。 我们将在体外和体外使用MS患者IFN β治疗前和治疗后的PBMNC研究这种调节作用的机制。 这些发现也将与MRI疾病活动相关。2.共聚物-I治疗MS的机制。我们将检查共聚物-1在从用该药物治疗的MS患者离体获得的PBMNC中的免疫学作用。 这包括共聚物-1特异性调节细胞的诱导，无论这些细胞是否与髓鞘抗原交叉反应并诱导细胞因子偏离，或者共聚物-1是否产生T细胞无反应性。拟议的研究可以帮助确定MS中与治疗反应相关的免疫网络的组成部分，因此有助于设计更有效的未来疗法。

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.