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、脱髓鞘和胶质细胞增多症为特征的临床神经系统疾病。它是成人早期和中期的主要神经系统疾病，在这个国家有多达35万人患有此病。可用于治疗和预防疾病进展的治疗方法有限。最近的证据表明，早期治疗干预在减少疾病活动性方面可能很重要。多发性硬化症至少部分由T细胞、巨噬细胞和少量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及其配体在体液免疫和细胞免疫调节中发挥着重要作用。阻断CD154可有效改善多种自身免疫性疾病的临床表现，已成为一个有吸引力的治疗靶点。CD40/CD40L的相互作用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都得到了证实。在EAE中，CD40L的抗体阻断在单相和复发缓解实验模型中都可以防止疾病的进展。这项临床研究试验的总体目标是确定CD40L抗体是否可以阻止复发-缓解型多发性硬化症(主要结果)患者MRI上强化病变的进展。临床定义为多发性硬化症(EDSS 0-小于3.5)的个人(n=40)将通过每月GdDTPA增强MRI扫描和EDSS进行为期6个月的评估，以确定疾病进展。如果符合条件(在6个月的治疗阶段中超过2个新的强化病变2 mm或更大)，这些患者(n=20-24)将接受静脉人源化抗CD40L(IDEC-131)治疗。患者将接受为期6个月(总共8次输注)的5 mg/kg抗体治疗，在此期间，他们将继续接受每月Gd增强MRI和EDSS评估(次要结果)。我们将确定治疗对磁共振波谱代谢的影响，NAA、胆碱和肌酸的峰值(绝对大小和比率)在左右半球脑室周围感兴趣的白质体素(次级结果)。将通过测定脑实质部分的变化来评估脑萎缩的延迟。我们还将开发一种新的生物检测方法来确定治疗效果(次要结果)。含有MBP多肽的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。结合MBP-MHCII-Ig的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认知障碍指数在治疗后的变化。对多发性硬化症临床试验结果敏感的神经心理变量包括视觉记忆和心理灵活性的测量。在登记后18个月和24个月进行MRI和EDSS随访(次要结果)。这项研究将使我们达到85%的能力(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).