Clinical, Immunopathogenic And Therapeutic Studies Of Sy

Sy 的临床、免疫致病性和治疗研究

• 批准号: 6668877
• 负责人: MICHAEL C SNELLER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6668877
• 关键词: Wegener's granulomatosis; antibody receptor; cardiovascular disorder chemotherapy; clinical trial phase I; combination chemotherapy; cytokine; cytokine receptors; flow cytometry; glucocorticoids; hormone therapy; human subject; human therapy evaluation; immunoglobulin G; longitudinal human study; methotrexate; microarray technology; mycophenolate mofetil; patient oriented research; vasculitis

We have previously demonstrated that therapy with cyclophosphamide (CP) was successful as a treatment for Wegener's granulomatosis (WG); however, drug toxicity has limited its use in many patients. Therefore, we evaluated the safety and efficacy of methotrexate (MTX) as an alternative therapy for WG. Results of these published studies demonstrated that MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. We have also investigated the potential for MTX to be used as maintenance therapy in patients in whom CP has induced a disease remission. In this protocol, patients receive prednisone plus CP therapy until remission of disease is achieved; CP is then switched to MTX for maintenance of remission. This CP/MTX regimen was highly effective and may represent a less toxic alternative to the standard CP regimen for patients with severe disease. We have also explored the use of other immunosuppressive drugs as remission maintenance agents. In a small open-label trial we investigated whether the immunosuppressive agent mycophenolate mofetil could be used in place of MTX for maintenance of CP-induced remission in patients with WG. Preliminary results of this study indicated that mycophenolate mofetil appeared to have efficacy in maintaining remission following CP therapy. In addition to these studies that utilize standard immunosuppressive drugs, we are also conducting 2 trials in patients with WG that utilized biologic agents that target specific cytokines involved in the inflammatory response. The first of these trials is designed to assess the safety, efficacy, and immunologic effects of a recombinant fusion protein that contains the extra cellular portion of the p75 TNF receptor linked to the Fc portion of human IgG1 (TNFR:Fc). We are seeking to examine whether TNFR:Fc is able to reduce the need for glucocorticoid treatment and lower relapse rates in patients with WG. The second trial investigates the safety and efficacy of daclizumab (a humanized monoclonal antibody that blocks the high-affinity interleukin-2 receptor on T cells) in the treatment of WG. This trial will seek to determine the efficacy of daclizumab in preventing disease relapses. In addition to our studies in WG we have recently initiated a phase I/I trial that will assess the safety and efficacy of Rituximab (a B cell depleting monoclonal antibody) in the treatment of patients with hepatitis C associated cryoglobulinemic vasculitis (HCV-CV).

我们以前已经证明，环磷酰胺（CP）治疗韦格纳肉芽肿（WG）是成功的，但药物毒性限制了它在许多患者中的使用。因此，我们评估了甲氨蝶呤（MTX）作为WG替代治疗的安全性和有效性。这些已发表的研究结果表明，MTX加泼尼松可能是一个可接受的替代形式的治疗选定的患者与WG。我们还研究了MTX作为CP诱导疾病缓解患者的维持治疗的潜力。在该方案中，患者接受泼尼松加CP治疗，直至疾病缓解;然后将CP转换为MTX以维持缓解。这种CP/MTX方案是非常有效的，并可能代表一种毒性较小的替代标准CP方案的严重疾病患者。我们还探索了使用其他免疫抑制药物作为缓解维持剂。在一项小型开放性试验中，我们研究了免疫抑制剂吗替麦考酚酯是否可以代替MTX用于维持WG患者CP诱导的缓解。这项研究的初步结果表明，霉酚酸酯似乎有疗效，维持缓解后CP治疗。除了这些使用标准免疫抑制药物的研究外，我们还在WG患者中进行了2项试验，这些试验使用了靶向参与炎症反应的特定细胞因子的生物制剂。这些试验中的第一项旨在评估重组融合蛋白的安全性、有效性和免疫学效应，该融合蛋白含有与人IgG 1 Fc部分连接的p75 TNF受体的细胞外部分（TNFR：Fc）。我们正在研究TNFR：Fc是否能够减少WG患者对糖皮质激素治疗的需求并降低复发率。第二项试验研究了达克珠单抗（一种阻断T细胞上高亲和力白细胞介素-2受体的人源化单克隆抗体）治疗WG的安全性和有效性。这项试验将寻求确定daclizumab在预防疾病复发方面的疗效。除了我们在WG中的研究，我们最近还启动了一项I/I期试验，该试验将评估利妥昔单抗（一种B细胞耗竭单克隆抗体）治疗丙型肝炎相关性冷球蛋白血症性血管炎（HCV-CV）患者的安全性和有效性。