Mechanisms of anti B cell therapy in SLE

SLE 抗 B 细胞治疗的机制

• 批准号: 6228084
• 负责人: ROBERT A. EISENBERG
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-28 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6228084
• 关键词: B lymphocyte; SCID mouse; disease /disorder model; human tissue; laboratory mouse; pathologic process; systemic lupus erythematosus

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.

SLE的当前疗法在很大程度上是非特异性和经验性的。人类疾病以及几种小鼠模型中的先前工作表明，B细胞在发病机理中起着核心作用。在本提案中，将通过平行研究在SLE的鼠模型（MRL/LPR）中研究抗B细胞疗法在SLE治疗中的疗效和机制；在人类中，包括在本应用中提出的临床方案中研究的患者；在小鼠/人类模型中，使用注射人PBL的SCID小鼠。在特定的目标1中，我们将确定如何从周围淋巴机器人器官中耗尽B细胞，以及在MRL/LPR小鼠模型中如何影响疾病。我们将确定B细胞将如何恢复，以及如何确保B细胞公差的维持。在赠款的人类部分中（特定目标2和特定目标3）我们将通过对患有SLE的人类的抗CD20治疗来阐明B细胞耗竭的机制，以及这种耗竭对B细胞和B细胞功能的影响在此类患者中有什么影响。预计在这些平行研究中获得的信息将决定B细胞耗竭如何成为现有SLE的有效疗法，并将帮助我们在SLE患者中修改B细胞耗竭的临床方案，并结合拟议的试验（Project 2，D。Albert，D。Albert，PI）。这将允许对这种新方法的治疗潜力进行彻底评估。