Mechanisms of anti B cell therapy in SLE

目前SLE的治疗方法大多是非特异性和经验性的。先前对人类疾病以及几种小鼠模型的研究表明，B细胞在其发病机制中起着核心作用。在本提案中，将通过SLE小鼠模型（MRL/lpr）的平行研究来研究抗b细胞治疗SLE的疗效和机制；在人类中，包括在本申请中提出的临床方案中研究的患者；以及在小鼠/人模型中使用SCID小鼠注射人PBL。在特异性目标1中，我们将确定如何从外周淋巴器官中消耗B细胞，以及这将如何影响MRL/lpr小鼠模型中的疾病。我们将决定B细胞如何恢复，以及我们如何确保维持B细胞的耐受性。在该资助的人类部分（Specific Aim 2和Specific Aim 3）中，我们将阐明抗cd20治疗SLE患者的B细胞消耗机制，以及这种消耗对此类患者的B细胞和B细胞功能的影响。预计在这些平行研究中获得的信息将确定b细胞消耗如何成为现有SLE的有效治疗方法，并将帮助我们结合拟议的试验修改SLE患者b细胞消耗的临床方案（项目2，D. Albert， PI）。这将允许对这种新方法的治疗潜力进行彻底的评估。

The current therapies for SLE are largely non-specific and empirical. Previous work in the human disease, as well as in several mouse models, has indicated that B cells play a central role in the pathogenesis. In the present proposal, the efficacy and mechanisms of anti-B cell therapy in the treatment of SLE will be investigated by parallel studies in a murine model for SLE (MRL/lpr); in humans, including the patients studied in the clinical protocol proposed in this application; and in a mouse/human model using SCID mice injected with human PBL. In Specific Aim 1, we will determine how we can deplete B cells from the peripheral lymphoid organs and how this will affect disease in the MRL/lpr mouse model. We will determine how B cells will recover, and how we can insure the maintenance of B-cell tolerance. In the human portion of the grant (Specific Aim 2 and Specific Aim 3) we will clarify the mechanisms of B-cell depletion with anti-CD20 therapy of humans with SLE, and what effect such depletion has on B cells and B-cell function in such patients. It is anticipated that the information obtained in these parallel studies will determine how B-cell depletion can be an effective therapy for existing SLE and will help us modify clinical protocols for B-cell depletion in SLE patients in conjunction with the proposed trials (Project 2, D. Albert, PI). This will permit a thorough evaluation of the therapeutic potential of this novel approach.