Mechanisms of anti B cell therapy in SLE

目前治疗系统性红斑狼疮的方法大多是非特异性的和经验性的。之前在人类疾病和几个小鼠模型中的研究表明，B细胞在发病机制中发挥着核心作用。在目前的提案中，将通过在SLE小鼠模型(MRL/LPR)、人类(包括在本申请中建议的临床方案中研究的患者)以及在使用SCID小鼠注射人PBL的小鼠/人模型中进行平行研究，来研究抗B细胞疗法在SLE治疗中的有效性和机制。在特定的目标1中，我们将确定如何从外周淋巴器官中去除B细胞，以及这将如何影响MRL/LPR小鼠模型中的疾病。我们将确定B细胞将如何恢复，以及我们如何确保维持B细胞的耐受性。在赠款的人类部分(特定目标2和特定目标3)，我们将阐明抗CD20治疗人类SLE的B细胞耗尽的机制，以及这种耗尽对此类患者的B细胞和B细胞功能有什么影响。预计在这些平行研究中获得的信息将确定B细胞耗竭如何成为现有SLE的有效治疗方法，并将帮助我们结合拟议的试验(项目2，D.阿尔伯特，PI)修改SLE患者B细胞耗尽的临床方案。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.