INTERFERON-B AND COPOLYMER-I IN MULTIPLE SCLEROSIS.

应聘者：应聘者是马里兰大学的神经学副教授，巴尔的摩退伍军人医学中心的神经科专家。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，申请者的实验室中有两个正在进行的研究项目：第一个是退伍军人管理局资助的优秀评审奖，将持续到2002年3月，以研究病毒在人类神经元中持续存在的机制；第二个是研究两种新批准的治疗多发性硬化症的药物的治疗机制，即IFNbeta和共聚物-1。在过去的6年里，四名博士后研究员在申请人的实验室进行了与多发性硬化症相关的研究。环境：马里兰州多发性硬化症中心在多发性硬化症的临床和基础研究方面获得国际认可，该中心的临床研究帮助FDA批准了目前上市的3种多发性硬化症药物中的2种，即倍他舒坦和共聚物-1。每年有800多名患者前来就诊，该中心还参与了几项多点临床试验。该中心由5名全职MS专家、3名护士和2名支持人员组成。研究：拟议的研究将侧重于了解贝塔斯隆和共聚物-1在MS中的治疗机制，目前这项研究的部分技术支持由贝莱克斯和Teva分别提供，贝莱克斯和Teva分别是贝塔斯隆和共聚物-1的制造商。1.检测干扰素β对MS患者IL-12的调节作用IL-12是参与MS发病机制的一种促炎细胞因子。初步研究表明，IFNβ对外周血单个核细胞(PBMNC)中的IL-12具有细胞特异性的调节作用。我们将在体外和体外使用多发性硬化症患者的PBMNC来研究这种调节作用的机制，这些患者在接受IFNβ治疗前后。这一发现还将与MRI疾病活动相关联。2.共聚物-I治疗多发性硬化症的机制我们将检测共聚物-1对多发性硬化症患者体外获得的PBMNC的免疫学效应。这包括诱导共聚物-1特异的调节细胞，这些细胞是否与髓鞘抗原发生交叉反应并诱导细胞因子偏离，或者共聚物-1是否产生T细胞无能。这项拟议的研究可能有助于确定MS中与治疗反应相关的免疫网络组件，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.