IMMUNE MECHANISMS OF ANTICD40L TRIAL IN SLE

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。

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.