ORAL IFN ALPHA--BIOLOGICAL EFFECTS IN MULTIPLE SCLEROSIS

描述(调查人员摘要)：我们将检查疗效和 口服干扰素-α降低干扰素的毒性作用 新的MRI(磁共振成像)脑损伤和IL-2的分泌， 复发缓解期患者干扰素-γ、白介素4、白介素10和转化生长因子-β的变化 多发性硬化(RR-MS)。肠外给药的一项最新研究 人重组人干扰素-β，1b在RR-MS中表明800万单位 HrIFN-β，1b S.C.每隔一天可以减少30%的复发， 减少脑部炎症和活动性病变的发生频率 序列定量磁共振成像。然而，40%的干扰素-β，1b治疗 患者会产生中和抗体，这种抗体可能更常见 在那些似乎同时失去临床益处和MRI定义的患者中 回应。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复发，减少丝裂原或抗原诱导 干扰素-γ分泌，口服给药更有效 预防急性或复发发作比同等剂量的S.C.干扰素-α 在这些MS动物模型中，过继转移活化的CD4+和CD8+ 给予干扰素-α的供体动物的T细胞抑制小鼠主动诱导的EAE 受者IL-4和IL-10水平升高。我们小组的最新数据 显示正常的人类志愿者摄取了30,000单位的 CD3介导的重组人干扰素-α产生较少的干扰素-γ 途径，早期RRMS摄入干扰素-α的受试者表现为减少 刀豆蛋白A介导的细胞增殖，降低IL-2、干扰素-γ、转化生长因子-β和IL-10 并降低血清中可溶性ICAM-1水平。此外，摄入的 干扰素-α提高干扰素诱导的小鼠脾细胞Mx相对mRNA水平 和人类外周血单核细胞，从而使研究 负责免疫调节的特定细胞靶点 摄入干扰素。这种待遇不太可能因为存在或存在而被废除 肠外可见循环中和抗体的诱导 干扰素-β。因此，口服干扰素-α疗法是一个独特的机会，可以模仿 临床缓解期多发性硬化症的细胞因子谱。 30名早期RR-MS患者至少通过一项筛查获得资格 单次入院前扫描的对比增强病变将在 隔日口服安慰剂的II期设计试验，或 Hr干扰素-α为10,000，或30,000个单位，每月使用脑Gd 增强的T1和多回波高分辨率平扫MRI扫描和 监测高达0.75的细胞因子和可溶性黏附分子水平 好几年了。结果衡量标准将是减少活动扫描的数量 使用MRI增强的自动化定量皮损评估。这个 口服干扰素-α对可溶性血清细胞间黏附分子的影响 1型干扰素特异性Mx mRNA的分子水平和诱导也将 评估过了。口服干扰素-α可提供更好的疗效和安全性 RR-MS和其他疾病与静脉注射1型干扰素的比较 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.