Clinical, Immunopathogenic And Therapeutic Studies Of Sy

Sy 的临床、免疫致病性和治疗研究

• 批准号: 6807873
• 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/6807873
• 关键词: Wegener's granulomatosis; antibody receptor; cardiovascular disorder chemotherapy; clinical trial phase I; combination chemotherapy; cyclophosphamide; 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; tumor necrosis factor alpha; vasculitis

The systemic vasculitides include a variety of generalized, life-threatening autoimmune diseases that have been studied for more than 30 years at the National Institutes of Allergy and Infectious Diseases. During this time large numbers of patients have been analyzed with regard to disease classification, pathophysiology, and treatment. We have previously demonstrated that the use of daily cyclophosphamide (CP) and glucocorticoids (GC) is highly effective therapy for Wegener's granulomatosis (WG). These studies pioneered the use of low-dose cytotoxic therapy as a treatment for life-threatening autoimmune diseases and our therapeutic protocol is used throughout the world. However, drug toxicity has limited use of this regimen in many patients. Thus, a major focus of this project has been to develop less toxic therapeutic regimens for the treatment of WG and related systemic vasculitis syndromes. Our approach to achieving this objective initially involved conducting a series of clinical trials that utilized less toxic conventional immunosuppressive regimens to induce and maintain remission. We have evaluated the safety and efficacy of methotrexate (MTX) as an alternative therapy for WG. Results indicate that low-dose weekly MTX is acceptable initial therapy for selected patients with WG who do not have immediately life-threatening disease and represents a less toxic alternative to standard CP therapy in this group of patients. We have also investigated the potential for MTX to be used as maintenance therapy in patients in whom CP has induced a disease remission. We have demonstrated that a cyclophosphamide induction-MTX maintenance regimen is highly effective and represents a less toxic alternative to the standard cyclophosphamide regimen for patients with severe disease. We have also explored the use 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. As a direct result of these studies, physicians now have available to them effective, less toxic regimens to use in the treatment of patients with WG. The increasing availability of biologic agents that modulate specific aspects of the immune response may soon make it possible to treat systemic vasculitis syndromes by selectively targeting pathogenic inflammation while leaving global host defense mechanisms intact. Along these lines, we are currently conducting two clinical trials in WG that employ specific cytokine antagonists. 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 (Etanercept). We are seeking to examine whether Etanercept is able to reduce the need for glucocorticoid treatment and lower relapse rates in patients with WG. The second trial will investigate 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 recently initiated a phase I/II 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). This disease occurs when an aberrant immune response to chronic HCV infection generates on oligoclonal expansion of B cells that produce IgM rheumatoid factor. The production of IgM rheumatoid factor leads to the formation of immune complexes consisting of HCV antigens, polyclonal HCV-specific IgG, and IgM rheumatoid factor. The deposition of these immune complexes in blood vessel walls triggers an inflammatory cascade that results in vasculitis. For the majority of patients with this disease there is no effective therapy. This protocol will test the hypothesis that treatment with Rituximab will deplete the oligoclonal population of B cells that are producing the pathogenic IgM rheumatoid factor that drives the immune-complex disease. Treatment with Rituximab should not alter the cell-mediated immune response to HCV, and thus should not exacerbate the liver disease.

系统性血管炎包括各种全身性的、危及生命的自身免疫性疾病，这些疾病已经在美国国立过敏和传染病研究所研究了30多年。在此期间，大量的患者已经分析了疾病分类，病理生理学和治疗。我们以前已经证明，每天使用环磷酰胺（CP）和糖皮质激素（GC）是韦格纳肉芽肿（WG）的高效治疗。这些研究开创了使用低剂量细胞毒性疗法治疗危及生命的自身免疫性疾病，我们的治疗方案在世界各地使用。然而，药物毒性限制了该方案在许多患者中的使用。因此，该项目的一个主要重点是开发毒性较小的治疗方案，用于治疗WG和相关的系统性血管炎综合征。我们实现这一目标的方法最初包括进行一系列临床试验，利用毒性较小的常规免疫抑制方案诱导和维持缓解。我们已经评估了甲氨蝶呤（MTX）作为WG的替代疗法的安全性和有效性。结果表明，低剂量每周MTX是可接受的初始治疗与WG谁没有立即危及生命的疾病，并代表了一个毒性较低的替代标准CP治疗在这组患者的选择。 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。我们已经证明，环磷酰胺诱导-MTX维持方案是非常有效的，是一种毒性较小的替代标准环磷酰胺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。作为这些研究的直接结果，医生现在可以使用有效的，毒性较小的方案来治疗WG患者。 调节免疫反应特定方面的生物制剂的日益增加的可用性可能很快使其有可能通过选择性靶向致病性炎症同时保持整体宿主防御机制完整来治疗系统性血管炎综合征。沿着这些路线，我们目前正在进行两项临床试验，在工作组采用特定的细胞因子拮抗剂。这些试验中的第一项旨在评估重组融合蛋白的安全性、疗效和免疫学效应，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（依那西普）。我们正在研究依那西普是否能够减少WG患者对糖皮质激素治疗的需求并降低复发率。第二项试验将研究Daclizumab（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，我们最近启动了一项I/II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）治疗丙型肝炎相关的冷球蛋白血症性血管炎（HCV-CV）患者的安全性和有效性。当对慢性HCV感染的异常免疫应答在产生IgM类风湿因子的B细胞的寡克隆扩增上产生时，这种疾病发生。IgM类风湿因子的产生导致由HCV抗原、多克隆HCV特异性IgG和IgM类风湿因子组成的免疫复合物的形成。这些免疫复合物在血管壁中的沉积触发了导致血管炎的炎症级联反应。对于大多数患有这种疾病的患者，没有有效的治疗方法。本方案将检验以下假设：利妥昔单抗治疗将耗尽产生致病性IgM类风湿因子的B细胞的寡克隆群体，该因子驱动免疫复合物疾病。利妥昔单抗治疗不应改变细胞介导的免疫反应，以丙型肝炎病毒，因此不应加重肝脏疾病。