Clinical/Immunopathogenic/Therapeutic Studies:Vasculitis

临床/免疫致病性/治疗研究：血管炎

• 批准号: 6506790
• 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/6506790
• 关键词: Wegener's granulomatosis; antibody receptor; cardiovascular disorder chemotherapy; clinical research; 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. In addition, 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. Based on these results, we have initiated a phase II randomized trial to assess the comparative efficacy of using MTX versus mycophenolate mofetil for maintaining remission that has been induced by CP and prednisone in patients with WG and related vasculitides. In studies of disease pathogenesis we have found that peripheral blood lymphocytes from patients with active WG produced 10 to 20- fold higher levels of interferon-gamma compared with peripheral blood lymphocytes from normal controls. Increased production of tumor necrosis factor (TNF) by CD4 T lymphocytes and IL-12 by purified monocytes were also noted, but production of IL-4, IL- 5, and IL-10 was not increased. Based on these findings, we have initiated a phase I/II trial 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.

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。此外，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。基于这些结果，我们启动了一项II期随机试验，以评估MTX与吗替麦考酚酯在WG和相关血管炎患者中维持CP和泼尼松诱导的缓解方面的比较疗效。 在疾病发病机制的研究中，我们发现，与正常对照组的外周血淋巴细胞相比，活动性WG患者的外周血淋巴细胞产生的干扰素-γ水平高10至20倍。还观察到CD 4 T淋巴细胞产生的肿瘤坏死因子（TNF）和纯化单核细胞产生的IL-12增加，但IL-4、IL- 5和IL-10的产生没有增加。基于这些发现，我们启动了一项I/II期试验，以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（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。