Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial
Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial
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DOI：
10.1001/archneur.64.10.nct70002
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发表时间：
2007-10-01
影响因子：
--
通讯作者：
Garren, Hideki
中科院分区：
文献类型：
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作者：
Bar-Or, Amit;Vollmer, Timothy;Garren, Hideki
目的：为了评估BHT-3009（一种编码全长人髓鞘碱性蛋白的耐受性DNA疫苗）在多发性硬化症（MS）患者中的安全性和免疫调节作用，设计：该研究是一项随机、双盲、安慰剂对照试验。接受安慰剂的受试者在治疗揭盲后交叉进入活性组。设置：试验在北美的4个学术机构进行。患者：30例复发缓解型或继发性进展型MS患者，未服用任何其他疾病调节药物，入选试验。此外，要求患者在筛选脑磁共振成像（MRI）时有1至5个钆增强病变，在过去2年内复发，或在过去2年内疾病恶化。干预措施：随机入组试验后第1、3、5和9周，肌肉注射BHT-3009，联合或不联合80 mg每日口服阿托伐他汀钙。测试了BHT-3009的三种剂量水平（0.5 mg、1.5 mg和3 mg）。主要结果测量：主要结果测量是BHT-3009的安全性和耐受性。次要结局指标包括MRI上钆增强病变的数量和体积、复发情况和抗原特异性免疫应答分析。结果：BHT-3009安全且耐受性良好，在脑MRI上提供了有利的趋势，并产生了有益的抗原特异性免疫变化。这些免疫变化包括外周血中产生干扰素-γ的髓鞘反应性CD 4 + T细胞增殖的显著减少和脑脊液中髓鞘特异性自身抗体滴度的减少，如通过蛋白质微阵列评估的。我们没有观察到阿托伐他汀组合与BHT-3009单独相比有实质性的益处。结论：在MS患者中，BHT-3009是安全的，并诱导抗原特异性免疫耐受，脑MRI上炎性病变一致减少。
Objective: To assess safety and immune modulation by BHT-3009, a tolerizing DNA vaccine encoding full-length human myelin basic protein, in patients with multiple sclerosis (MS).Design: The study was a randomized, double-blind, placebo-controlled trial. Subjects receiving placebo were crossed over into an active arm after treatment unblinding.Setting: The trial was conducted at 4 academic institutions within North America.Patients: Thirty patients with relapsing-remitting or secondary progressive MS who were not taking any other disease-modifying drugs were enrolled in the trial. Further, the patients were required to have either 1 to 5 gadolinium-enhancing lesions on screening brain magnetic resonance imaging (MRI), a relapse in the previous 2 years, or disease worsening in the previous 2 years.Interventions: BHT-3009 was administered as intramuscular injections at weeks 1, 3, 5, and 9 after randomization into the trial, with or without 80 mg of daily oral atorvastatin calcium in combination. Three dose levels of BHT-3009 were tested (0.5 mg, 1.5 mg, and 3 mg).Main Outcome Measures: The primary outcome measures were safety and tolerability of BHT-3009. Secondary outcome measures included the number and volume of gadolinium-enhanced lesions on MRI, relapses, and analysis of antigen-specific immune responses.Results: BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI, and produced beneficial antigen-specific immune changes. These immune changes consisted of a marked decrease in proliferation of interferon-gamma-producing, myelinreactive CD4+ T cells from peripheral blood and a reduction in titers of myelin-specific autoantibodies from cerebral spinal fluid as assessed by protein microarrays. We did not observe a substantial benefit of the atorvastatin combination compared with BHT-3009 alone.Conclusion: In patients with MS, BHT-3009 is safe and induces antigen-specific immune tolerance with concordant reduction of inflammatory lesions on brain MRI.