MULTIPLE-SCLEROSIS: A CD40 LIGAND ANTAGONIST

多发性硬化症（MS）是一种以中枢神经系统慢性炎症、脱髓鞘和胶质瘤为特征的临床神经系统疾病。它是成年早期到中期个体的主要神经系统疾病，在这个国家有多达35万人受到折磨。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，早期治疗干预可能对降低疾病活动性很重要。MS至少部分由T细胞、巨噬细胞介导，在较小程度上由B细胞介导。T细胞和B细胞的激活依赖于TCR/MHC以及包括CD40-CD40L在内的共刺激分子的相互作用。CD40及其配体已被证明在调节体液和细胞介导的免疫中发挥关键作用。阻断CD154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。CD40/CD40L的相互作用已在实验性变应性脑脊髓炎（EAE）和多发性硬化症的实验模型中得到证实。在EAE中，CD40L的抗体阻断在单相和复发缓解型实验模型中都可以阻止疾病的进展。这项临床研究试验的总体目的是确定CD40L抗体是否可以阻断复发-缓解型MS患者MRI强化病变的进展（主要结局）。临床定义为MS （EDSS 0-小于3.5）的个体（n=40）将通过每月GdDTPA增强MRI扫描和EDSS评估6个月，以确定疾病进展。如果符合条件（在6个月的预处理阶段大于2个新的增强病变2mm或更大），这些个体（n=20-24）将接受静脉注射人源化抗cd40l （IDEC-131）治疗。患者将接受5mg/kg抗体治疗6个月（共8次输注），在此期间，他们将继续每月接受Gd增强MRI和EDSS评估（次要结局）。我们将确定治疗对磁共振光谱代谢的影响，对左右半球感兴趣的脑室周围白质体素中NAA、胆碱和肌酸的峰值（绝对值和比值）的影响（次要结果）。脑实质分数的变化可以判断脑萎缩的延迟。我们还将开发一种新的生物检测方法来确定治疗的疗效（次要结局）。具有嵌入MBP肽的MHCII-Ig融合蛋白将用于识别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被确定。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，以及T和B细胞对破伤风类毒素的召回，将在体外确定。另一个次要结果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心理灵活性的测量。随访将在入组后18个月和24个月进行MRI和EDSS（次要结局）。这项研究将使我们达到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).