IMMUNE MECHANISMS OF ANTICD40L TRIAL IN SLE

SLE 中 ANTICD40L 试验的免疫机制

• 批准号: 6341792
• 负责人: SYAMAL K DATTA
• 金额: $ 22.83万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-25 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6341792
• 关键词: B lymphocyte; CD40 molecule; T lymphocyte; antiantibody; antinuclear autoantibody; cellular immunity; clinical research; clinical trials; drug screening /evaluation; human subject; humoral immunity; nephritis; systemic lupus erythematosus

DESCRIPTION (Verbatim from Investigator's abstract): Our main objective is to study the basic immunologic mechanisms underlying the therapeutic effects of a humanized anti-CD40 ligand antibody (anti-CD40L, BG9588) administered into patients with active lupus nephritis. A total of about 120 patients in 28 centers are participating in this randomized, double- blind, controlled, multiple-dose study of anti-CD40L (BG9588) sponsored by Biogen Inc. Molecular interactions between CD40L and CD40 provides essential costimulatory signals for humoral and cellular immune responses. Most remarkably, CD40L is hyperexpressed by lupus T and B cells for abnormally prolonged periods -- thus sustaining the production of pathogenic autoantibodies. Moreover, a brief therapy of three- injections of anti-CD40L in one week into lupus mice prevents the development of nephritis for more than a year. The mechanism of such a long-term benefit, which is equivalent to 3-4 decades in humans, is unknown. This clinical trial provides an unprecedented opportunity to study the effects of anti-CD40L on the human immune system in vivo, particularly on the cells participating in the chronic ongoing autoimmune response in lupus patients. We will study the status of autoimmune T and B cells that are involved in the production of pathogenic anti-nuclear autoantibodies, before, during and after therapy to answer the following questions: I. Are autoimmune T cells, particularly the ones that respond to nucleosomal peptides and drive the production of pathogenic anti-DNA autoantibodies, deleted or anergized in the anti-CD40L treated patients? II. Are autoimmmune B cells of lupus that make pathogenic autoantibodies and are nucleosome-specific, deleted or anergized by anti-CD40L therapy? III. Are regulatory T cells that could suppress autoantibody production, generated by anti-CD40L therapy? We expect to know more about the workings of the normal and lupus immune systems in humans from these studies.

描述(逐字摘自调查者摘要)：我们的主要目标 是为了研究治疗的基本免疫学机制 人源化抗CD40配体抗体(抗CD40L、BG9588)的作用 用于活动性狼疮性肾炎患者。总共约有 来自28个中心的120名患者参加了这项随机、双盲、 抗CD40L(BG9588)多剂量盲法对照研究 CD40L和CD40之间的分子相互作用提供了 体液免疫和细胞免疫的基本共刺激信号 回应。最值得注意的是，CD40L在狼疮T和B细胞中高表达 异常长时间的细胞--从而维持生产 致病的自身抗体。此外，三个方面的简单疗法-- 狼疮小鼠一周内注射抗CD40L可预防 发展为肾炎一年多。这样的一种机制 相当于人类3-40年的长期益处是 未知。这项临床试验提供了一个前所未有的机会 体内研究抗CD40L对人体免疫系统的影响 尤其是参与慢性进行中的细胞 狼疮患者的自身免疫反应。我们将研究 自身免疫T细胞和B细胞参与产生 治疗前、治疗中和治疗后的致病性抗核自身抗体 回答以下问题：一是自身免疫T细胞， 尤其是那些对核小体肽有反应并驱动 致病性抗DNA自身抗体的产生，缺失或缺失 在抗CD40L治疗的患者中？二、狼疮自身免疫的B细胞 产生致病性自身抗体，并且是核小体特异性的，被删除 还是被抗CD40L治疗所麻木？三、调节性T细胞 能抑制由抗CD40L治疗产生的自身抗体产生吗？ 我们希望更多地了解正常免疫和狼疮免疫的工作原理。 来自这些研究的人体系统。