SPECIFIC IMMUNOTHERAPY OF MYASTHENIA--SAFE STRATEGIES

肌无力的特异性免疫治疗——安全策略

• 批准号: 2704126
• 负责人: DANIEL B DRACHMAN
• 金额: $ 24.48万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2704126
• 关键词: T lymphocyte; blocking antibody; chemical conjugate; cholinergic receptors; diphtheria toxin; immunotherapy; interleukin 2; laboratory rat; myasthenia gravis; nonhuman therapy evaluation; recombinant proteins; tissue /cell culture

DESCRIPTION: The pathogenesis of myasthenia gravis (MG) involves an antibody-mediated autoimmune response directed against acetylcholine receptors (AChR). Although current treatment of MG with immunosuppressive agents is reasonably effective, it has important drawbacks, including overall suppression of the immune system, and other adverse side effects. The goal of specific immunotherapy has remained elusive. Since the pathogenic AChR antibody response is T cell dependent, inactivation or elimination of AChR-specific T cells interrupts the immune response, with resulting clinical benefit. However, the fact that T cell responses to AChR are highly heterogeneous presents a strategic problem in designing specific immunotherapy. This proposal will explore and capitalize on a novel strategy of safe stimulation to target the entire spectrum of AChR-specific T cells, using denatured AChR (denAChR), in conjunction with genetically engineered agents that inactivate and/or eliminate the specifically stimulated T cells. The studies will be carried out in Lewis rats with experimental autoimmune MG (EAMG). DenAChR stimulates AChR-specific T cells as strongly as native AChR, but its reduced and non-pathogenic AChR antibody response avoids the risk of exacerbating MG. Stimulation is a necessary condition for the action of the therapeutic agents. CTLA4Ig is a soluble recombinant protein that blocks the B7 family of costimulatory molecules, and may induce anergy in antigen-stimulated T cells. Preliminary studies suggest that CTLA4Ig prevents primary EAMG and inhibits secondary EAMG, with interesting changes in the AChR antibody isotypes, suggestive of a switch in T helper cells from Th1 to Th2 type. DAB389IL2 is a fusion protein that binds to IL2 receptors on antigen-activated T cells, and kills them via a lethal diphtheria toxin moiety. Preliminary studies using DAB389IL2 in vitro and in vivo show marked inhibition of immune responses to AChR. Combined use of CTLA4Ig + DAB389IL2 appears to be even more potent, with a powerful effect on the difficult-to-treat secondary immune response to AChR. We will study the effects of this strategy on antibodies to Torpedo and autoantibodies to rat

描述：肌无力重症（Mg）的发病机理涉及 针对乙酰胆碱的抗体介导的自身免疫反应 受体（ACHR）。 尽管当前用免疫抑制治疗MG 代理商是相当有效的，它具有重要的缺点，包括 免疫系统的总体抑制和其他不良副作用。 特定免疫疗法的目标仍然难以捉摸。 自从 致病性ACHR抗体反应是T细胞依赖性，失活或 消除ACHR特异性T细胞会中断免疫反应，并使用 由此产生的临床益处。 但是，T细胞对ACHR的反应这一事实 高度异质提出了设计特定的战略问题 免疫疗法。 该建议将探索并大写一本小说 安全刺激的策略，以针对全部ACHR特异性范围 T细胞，使用变性ACHR（DENACHR）与遗传学结合 灭活和/或具体消除的工程剂 刺激的T细胞。 研究将在刘易斯大鼠中进行 实验自身免疫性MG（EAMG）。 Denachr刺激ACHR特异性T细胞 与天然ACHR一样强，但其降低和非致病ACHR抗体 响应避免了加剧毫克的风险。 刺激是必要的 治疗剂作用的条件。 ctla4ig是可溶的 重组蛋白阻断B7的共刺激分子家族， 并可能诱导抗原刺激的T细胞中的Anergy。 初步研究 建议CTLA4IG阻止主要EAMG并抑制次级EAMG，并使用 ACHR抗体同型的有趣变化，表明开关 T辅助细胞从Th1到Th2型。 DAB389IL2是一种融合蛋白 在抗原激活的T细胞上与IL2受体结合，并通过A杀死它们 致命的白喉毒素部分。 使用DAB389IL2在 体外和体内显示对ACHR免疫反应的明显抑制。 CTLA4IG + DAB389IL2的联合使用似乎更有效， 对难以治疗的二级免疫反应的强大影响。 我们将研究该策略对鱼雷抗体的影响和 自身对老鼠的抗体