IMMUNE MECHANISMS OF ANTICD40L TRIAL IN SLE

SLE 中 ANTICD40L 试验的免疫机制

• 批准号: 6137339
• 负责人: SYAMAL K DATTA
• 金额: $ 22.3万
• 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/6137339
• 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（逐字摘自研究者摘要）：我们的主要目的 是研究治疗的基本免疫机制， 人源化抗CD 40配体抗体（抗CD 40 L，BG 9588）的作用 狼疮性肾炎的症状有哪些？共约 来自28个中心的120名患者参与了这项随机、双 申办的抗CD 40 L（BG 9588）设盲、对照、多次给药研究 关于Biogen Inc. CD 40 L和CD 40之间的分子相互作用提供了 体液和细胞免疫的必需共刺激信号 应答最值得注意的是，T型和B型狼疮高表达CD 40 L 细胞异常延长的时间-从而维持生产 致病性自身抗体此外，一个简短的治疗三- 在一周内向狼疮小鼠注射抗CD 40 L可以防止 肾炎的发展超过一年。这种机制 长期受益，相当于人类的3-4年， 未知这项临床试验提供了前所未有的机会， 研究抗CD 40 L对人体免疫系统的影响， 特别是对参与慢性持续性 狼疮患者的自身免疫反应我们将研究 自身免疫性T和B细胞参与产生 治疗前、治疗中和治疗后的病原性抗核自身抗体 回答以下问题：一。是自身免疫性T细胞， 特别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，缺失或无反应 抗CD 40 L治疗的患者中，？二.是狼疮的自身免疫B细胞 产生致病性自身抗体的核小体特异性基因， 还是抗CD 40 L治疗导致无反应三.是调节性T细胞 是否可以抑制抗CD 40 L治疗产生的自身抗体？ 我们希望更多地了解正常和狼疮免疫系统的工作原理， 这些研究中的人类系统。