MULTIPLE-SCLEROSIS: A CD40 LIGAND ANTAGONIST

多发性硬化（MS）是一种以中枢神经系统慢性炎症、脱髓鞘和胶质增生为特征的临床神经系统疾病。 它是成年早期至中期个体的主要神经系统疾病，在这个国家折磨着多达35万人。 用于治疗和预防疾病进展的可用疗法是有限的。 最近的证据表明，早期治疗干预可能是重要的，在减少疾病的活动。 MS至少部分由T细胞、巨噬细胞介导，并且在较小程度上由B细胞介导。 T和B细胞的活化依赖于TCR/MHC以及共刺激分子（包括CD 40-CD 40 L）的相互作用。 CD 40及其配体已被证明在体液和细胞介导的免疫调节中起关键作用。 阻断CD 154可有效改善多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。 在实验性变态反应性脑脊髓炎（EAE）和多发性硬化症的实验模型中均证实了CD 40/CD 40 L的相互作用。 在EAE中，CD 40 L的抗体阻断在双相和复发缓解实验模型中均阻止疾病进展。本临床研究试验的总体目标是确定CD 40 L抗体是否可以阻断复发缓解型MS患者MRI上增强病变的进展（主要结局）。 将通过每月一次的GdDTPA增强MRI扫描和EDSS对临床定义的MS（EDSS 0-小于3.5）个体（n=40）进行为期6个月的评估，以确定疾病进展。 如果符合条件（6个月预治疗期内大于或等于2个新增强病灶），这些个体（n=20-24）将接受静脉内人源化抗CD 40 L（IDEC-131）治疗。 患者将用5 mg/kg抗体治疗6个月（总共=8次输注），在此期间，他们将继续接受每月一次的Gd增强MRI和EDSS评价（次要结局）。 我们将确定治疗对感兴趣的左右半球脑室周围白色物质体素的MR波谱代谢、NAA、胆碱和肌酸峰值（绝对幅度和比率）的影响（次要结局）。 将通过确定脑实质分数的变化来评价脑萎缩的延迟。 我们还将开发一种新的生物测定法，以确定治疗的疗效（次要结局）。 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。将确定MBP-MHCII-IG结合T细胞的极性（Th 1和Th 2）以及它们的活化状态。 将在体外确定体内抗-CD 40 L治疗对MBP-MHCII-IG结合T细胞的频率、表型和功能状态的影响以及T和B细胞对破伤风类毒素的回忆。 另一个次要结局是评估治疗后认知障碍指数的变化。对MS临床试验结果敏感的神经心理学变量包括视觉记忆和精神灵活性的测量。将在入组后18个月和24个月进行MRI和EDSS随访（次要结局）。 这项研究将使我们能够实现85%的功效（减少32%的斑块负担）。

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).