MULTIPLE-SCLEROSIS: A CD40 LIGAND ANTAGONIST

多发性硬化症：CD40 配体拮抗剂

• 批准号: 6540383
• 负责人: LLOYD H KASPER
• 金额: $ 77.5万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540383
• 关键词: CD40 molecule; T lymphocyte; behavioral /social science research tag; bioassay; brain imaging /visualization /scanning; disease /disorder prevention /control; functional ability; human subject; human therapy evaluation; immunoregulation; inhibitor /antagonist; leukocyte activation /transformation; ligands; magnetic resonance imaging; monoclonal antibody; multiple sclerosis; nervous system disorder chemotherapy; neuritic plaques; neuropsychological tests; neuropsychology; patient oriented research; psychometrics; questionnaires; relapse /recurrence; technology /technique development

Multiple sclerosis (MS) is a clinical neurological disease characterized by chronic inflammation, demyelination and gliosis of the central nervous system. It is the principal neurologic disease of individuals in early to middle adult life and afflicts as many as 350,000 people in this country. The available therapy for treating and preventing the progression of disease is limited. Recent evidence suggests that early therapeutic intervention may be important in decreasing disease activity. MS is mediated at least in part by T cells, macrophages and to a lesser extent B cells. Activation of T and B cells is dependent upon the interaction of the TCR/MHC as well as co-stimulatory molecules, including CD40-CD40L. CD40 and its ligand have been shown to play a critical role in the regulation of both humoral and cell-mediated immunity. Blockade of CD154 is effective in ameliorating the manifestations of several autoimmune diseases and thus has become an attractive therapeutic target. The interaction of CD40/CD40L has been demonstrated in both the experimental model of experimental allergic encephalomyelitis (EAE) as well as multiple sclerosis. In EAE, antibody blocking of CD40L prevents the progression of disease in both the monophasic and relapsing remitting experimental models. The overall objective of this clinical research trial is to determine whether antibody to CD40L can block the progression of enhancing lesions on MRI in those individuals with relapsing- remitting MS (primary outcome). Individuals (n=40) with clinically defined MS (EDSS 0-less than 3.5) will be evaluated for six months by monthly GdDTPA enhanced MRI scans and EDSS to determine disease progression. If eligible (greater than 2 new enhancing lesion 2mm or greater during the 6 month pretreatment phase), these individuals (n=20-24) will be treated with intravenous humanized anti-CD40L (IDEC-131). Patients will be treated for 6 months (total=8 infusions) with 5mg/kg antibody during which time they will continue to undergo monthly Gd enhanced MRI and EDSS evaluation(secondary outcome). We will determine the effect of therapy on MR spectroscopy metabolic, peaks for NAA, choline and creatine (absolute magnitude and ratios) in left and right hemispheric periventricular white matter voxels of interest (secondary outcome). Delay in cerebral atrophy will be evaluated by determining the change in parenchymal brain fraction. We will also develop a novel biological assay to determine efficacy of therapy(secondary outcome). MHCII-Ig fusion proteins that have an embedded MBP peptide will be used to identify MBP-reactive T cells in the peripheral blood of these patients. The polarity (Th1 and Th2) of the MBP-MHCII-Ig binding T cells will be determined as well as their activation status. The impact of in vivo anti-CD40L therapy on the frequency, phenotype and functional status of the MBP-MHCII-Ig binding T cells will be determined in vitro as well as T and B cell recall to tetanus toxoid. An additional secondary outcome will be to assess change in the cognitive impairment index in response to therapy. Neuropsychological variables sensitive to clinical trial outcomes in MS include measures of visual memory and mental flexibility. Follow up will be done with MRI and EDSS at 18 and 24 months after enrollment(secondary outcome). The study will will allow us to achieve a power of 85 percent (32 percent reduction in plaque burden).

多发性硬化症（MS）是一种临床神经系统疾病，其特征是中枢神经系统的慢性炎症，脱髓鞘和神经胶质病。 它是成人早期至中期的个体的主要神经疾病，在这个国家遭受了35万人的折磨。 可用治疗和预防疾病进展的可用疗法受到限制。 最近的证据表明，早期的治疗干预对于减少疾病活动可能很重要。 MS至少部分由T细胞，巨噬细胞和较小程度的B细胞介导。 T和B细胞的激活取决于TCR/MHC以及包括CD40-CD40L在内的共刺激分子的相互作用。 CD40及其配体已显示在调节体液和细胞介导的免疫力中起关键作用。 CD154的封锁可有效改善几种自身免疫性疾病的表现，因此已成为一个有吸引力的治疗靶点。 在实验性过敏性脑脊髓炎（EAE）的实验模型和多发性硬化症的实验模型中，CD40/CD40L的相互作用均已证明。 在EAE中，CD40L的抗体阻断可防止单相和复发的恢复实验模型的疾病进展。这项临床研究试验的总体目的是确定对CD40L的抗体是否可以阻止那些患有复发性恢复MS的人（主要结果）的MRI增强病变的进展。 通过临床定义的MS（EDSS 0- 3.5）的个体（n = 40）将通过每月GDDTPA进行六个月的评估，以增强MRI扫描和EDSS，以确定疾病进展。 如果符合条件（在6个月预处理阶段大于2毫升2mm或更高的新增强病变），这些人（n = 20-24）将用静脉内人性化抗CD40L（IDEC-131）进行处理。 患者将接受5mg/kg抗体的治疗6个月（总计8个输注），在此期间，他们将继续每月接受GD增强的MRI和EDSS评估（次要结果）。 我们将确定治疗对MR光谱代谢的影响，NAA的峰，胆碱和肌酸（绝对幅度和比率）在左右半球周围白质白质体素（第二结果）。 通过确定实质脑部分的变化，将评估脑萎缩的延迟。 我们还将开发一种新型的生物学测定，以确定治疗的功效（次要结果）。 具有嵌入的MBP肽的MHCII-IG融合蛋白将用于鉴定这些患者外周血中的MBP反应性T细胞。 MBP-MHCII-Ig结合T细胞的极性（Th1和Th2）以及它们的激活状态将确定。 体内抗CD40L治疗对MBP-MHCII-IG结合T细胞的频率，表型和功能状态的影响将在体外确定，以及T和B细胞回忆对破伤风毒素。 另一个次要结果将是评估对治疗的认知障碍指数的变化。对MS的临床试验敏感的神经心理变量包括视觉记忆和心理灵活性的度量。在入学后18到24个月（次要结果）的MRI和EDSS进行跟进。 这项研究将使我们能够实现85％的能力（斑块负担减少了32％）。