ORAL IFN ALPHA--BIOLOGICAL EFFECTS IN MULTIPLE SCLEROSIS

描述（研究者摘要）：我们将检查疗效， 口服干扰素-α（IFN-α）降低 新的MRI（磁共振成像）脑病变和IL-2分泌， 复发-缓解型乳腺癌患者的IFN-γ、IL-4、IL-10和TGF-β 多发性硬化症（RR-MS）。 最近一项研究表明， RR-MS中人重组hrIFN-β，1b表明800万单位 hrIFN-β，1b s.c.每隔一天可以减少30%的复发率， 减少脑部炎症和活动性病变的频率， 通过连续定量MRI。 然而，40%的IFN-β，1b治疗 患者产生的中和抗体可能更常见于 在那些似乎失去临床获益和MRI定义的患者中， 应答 我们已经证明，口服1型干扰素可以 预防急性实验性自身免疫性脑脊髓炎（EAE），抑制 慢性复发性EAE的复发，减少丝裂原或抗原诱导 IFN-γ分泌，口服给药更有效， 预防急性或复发性发作的效果优于同等剂量的皮下注射。IFN-alpha 在这些MS动物模型中，活化的CD 4+和CD 8+的连续转移 来自IFN-α喂养的供体动物的T细胞抑制小鼠中主动诱导的EAE。 增加IL-4和IL-10。 我们集团的最新数据 表明正常人志愿者受试者摄入30，000单位的 人重组IFN-α通过CD3介导产生较少的IFN-γ 在IFN-α通路中，早期RRMS受试者的IFN-α水平降低， Con A介导的增殖，降低IL-2、IFN-γ、TGF-β和IL-10 分泌，并降低血清可溶性ICAM-1水平。 此外，摄入 IFN-α增加小鼠脾细胞中IFN诱导的Mx mRNA相对水平 和人外周血单核细胞，从而允许研究 负责免疫调节的特异性细胞靶点由 摄入干扰素。 这种待遇不太可能被废除的存在或 在胃肠外感染中观察到的循环中和IFN抗体的诱导 IFN-β 因此，口服IFN-α治疗是一个独特的机会，模拟 MS临床缓解期的细胞因子谱。 30例早期RR-MS患者接受了至少一项合格性筛选 对比增强病变的一个单一的预进入扫描，将研究在一个 隔日口服安慰剂的II期设计试验，或 hrIFN-α 10，000或30，000单位，每月脑钆 增强T1和多回波高分辨率非增强MRI扫描， 监测细胞因子和可溶性粘附分子水平达0.75 年 结果指标将是活动扫描次数的减少 使用MRI增强的自动定量损伤评估。 的 摄入IFN-α治疗对可溶性血清细胞间质 分子水平和1型IFN特异性Mx mRNA的诱导也将被 评估。 摄入的IFN-α可提供上级疗效和安全性， 在RR-MS和其他研究中与胃肠外给药的1型IFN的比较 自身免疫性疾病

DESCRIPTION (Investigator's Abstract): We will examine the efficacy and toxicity of orally administered interferon-alpha (IFN-alpha) in decreasing new MRI (Magnetic Resonance Imaging) brain lesions and secretion of IL-2, IFN-gamma, IL-4, IL-10 and TGF-beta in patients with relapsing-remitting multiple sclerosis (RR-MS). A recent study of parenterally administered human recombinant hrIFN-beta,1b in RR-MS suggest that 8 million units of hrIFN-beta,1b s.c. every other day can decrease relapses by 30 percent, decrease brain inflammation and the frequency of active lesions as accessed by serial quantitative MRI. However 40 percent of IFN-beta,1b treated patients generated neutralizing antibodies that may be more frequently found in those patients who appear to lose both clinical benefits and MRI defined responses. We have shown that the oral administration of type-1 IFNs can prevent acute experimental autoimmune encephalomyelitis (EAE), suppress relapses in chronic relapsing EAE, decrease mitogen or antigen induced IFN-gamma secretion, and that oral administration is more effective in preventing acute or relapse attacks than equivalent doses of s.c. IFN-alpha in these animal models of MS. Adoptive transfer of activated CD4+ and CD8+ T cells from IFN-alpha fed donor animals inhibits actively induced EAE in recipients by increased IL-4 and IL-10. Recent data from our group demonstrates that normal human volunteer subjects ingesting 30,000 units of human recombinant IFN-alpha produce less IFN-gamma via the CD3 mediated pathway, subjects with early RRMS ingesting IFN-alpha demonstrate decreased Con A-mediated proliferation, decreased IL-2, IFN-gamma, TGF-beta and IL-10 secretion, and decreased soluble serum ICAM-1 levels. In addition, ingested IFN-alpha increased relative IFN-induced Mx mRNA levels in mouse splenocytes and human peripheral mononuclear cells, thereby allowing an investigation of the specific cell target responsible for immunomodulation induced by ingested IFN. This treatment is unlikely to be abrogated by the presence or induction of circulating neutralizing IFN antibodies seen in parenteral IFN-beta. Thus, oral IFN-alpha therapy a unique opportunity to mimic the cytokine profile of MS in clinical remission. Thirty patients with early RR-MS screened for eligibility by at least one contrast enhancing lesion on a single pre-entry scan, will be studied in a Phase II design trial of alternate day orally administered placebo, or hrIFN-alpha at 10,000, or 30,000 units with monthly brain gadolinium enhanced T1 and multi-echo high resolution unenhanced MRI scans and monitoring of cytokine and soluble adhesion molecule levels for up to 0.75 years. Outcome measures will be decreases in the number of active scans using automated quantitative lesional assessment of MRI enhancements. The effect of ingested IFN-alpha treatment on soluble serum intercellular molecules level and induction of Type-1 IFN-specific Mx mRNA will also be assessed. Ingested IFN-alpha may provide superior efficacy and safety in comparison to parenteral administered Type-1 IFNs in RR-MS and other autoimmune diseases.