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（研究者摘要中的逐字记录）：我们的主要目标 是研究治疗背后的基本免疫机制 人源化抗 CD40 配体抗体（抗 CD40L、BG9588）的作用 给予活动性狼疮肾炎患者。总共约 28 个中心的 120 名患者参与了这项随机、双 赞助的抗 CD40L (BG9588) 盲法、对照、多剂量研究 CD40L 和 CD40 之间的分子相互作用提供了 体液和细胞免疫的重要共刺激信号 回应。最值得注意的是，CD40L 在 T 型狼疮和 B 型狼疮中过度表达 细胞异常延长的时间——从而维持生产 致病性自身抗体。此外，短期治疗三 狼疮小鼠一周内注射抗 CD40L 可预防 患肾炎一年多了。这样的机制 长期效益相当于人类 3-4 年的效益 未知。这项临床试验提供了前所未有的机会 研究抗CD40L对体内人体免疫系统的影响， 特别是参与慢性正在进行的细胞 狼疮患者的自身免疫反应。我们将研究现状 参与生产的自身免疫 T 和 B 细胞 治疗前、治疗期间和治疗后的致病性抗核自身抗体 回答以下问题： I. 是自身免疫 T 细胞吗？ 特别是那些对核小体肽做出反应并驱动 产生致病性抗 DNA 自身抗体，删除或激活 在接受抗CD40L治疗的患者中？二.狼疮的自身免疫B细胞是吗 产生致病性自身抗体并且是核小体特异性的，被删除 或通过抗CD40L疗法激活？三．调节性 T 细胞是 可以抑制抗 CD40L 治疗产生的自身抗体的产生吗？ 我们希望更多地了解正常免疫和狼疮免疫的工作原理 从这些研究中得出的人类系统。