Experimental Induction of SLE by Altered Ia

描述（申请人提供）：B细胞耐受性丧失是SLE自身免疫发病机制的核心。为了探讨这一过程中涉及的机制，我们利用了慢性移植物抗宿主模型的SLE，其中我们转移MHC II类不相容的bm 12脾细胞或纯化的CD 4脾T细胞C57 BL/6小鼠，利用各种受体转基因变异。该系统使我们能够详细研究B细胞耐受性丧失的机制，这是SLE的特征。我们以前在这个项目上的工作和我们最近的初步数据已经确定了我们建议在当前应用中追求的几个令人兴奋的方向。我们将解决的问题，如：为什么SLE使B细胞耐单克隆抗体耗尽？受体编辑和等位基因包含在B细胞耐受性丧失中起什么作用？CD 4 T细胞如何控制B细胞的个体发育，使它们能够对同种异体反应性T细胞产生反应？自身抗体形成细胞的表型和分布是什么，与临床疾病有什么关系？我们将继续这项工作，有四个具体的目标：（1）什么是B细胞耗竭作为一个潜在的治疗SLE的机制？(2)在个体发育的哪个阶段，B细胞会失去耐受性？(3)CD 4 T细胞如何影响B细胞的个体发育？(4)SLE中的自身抗体形成细胞在哪里，特别是肾脏？ 更好地理解B细胞在系统性自身免疫中的作用和B细胞耗竭的治疗效果将允许更有效地使用现有的B细胞靶向疗法，如利妥昔单抗，以及更合理地开发更新的B细胞疗法或疗法组合。很可能需要鉴定新的生物标志物，以允许合理监测B细胞定向治疗和适当选择可能应答的患者。本计画将使用一种复杂自体免疫疾病系统性红斑狼疮的实验小鼠模型。这些研究将特别调查参与这种疾病的关键细胞之一的作用：B淋巴细胞。所获得的知识将提高我们对系统性红斑狼疮发病机制的了解，以及我们如何在治疗中靶向B淋巴细胞。

DESCRIPTION (provided by applicant): The loss of B-cell tolerance is central to the pathogenesis of autoimmunity in SLE. In order probe the mechanisms involved in this process, we have utilized the chronic graft versus host model of SLE in which we transfer MHC class II-incompatible bm12 spleen cells or purified CD4 splenic T cells to C57BL/6 mice, utilizing various recipient transgenic variants. This system allows us to investigate in detail the mechanism of loss of B-cell tolerance that characterizes SLE. Our previous work on this project and our recent preliminary data has identified several exciting directions that we are proposing to pursue in the current application. We will address questions such as: Why does SLE make B cells resistant to depletion with mAb? What role does do receptor editing and allelelic inclusion play in the loss of B cell tolerance? How do CD4 T cells control the ontogeny of B cells, so that they can respond to alloreactive T cells? What is the phenotype and distribution of autoantibody forming cells, and how does that relate to clinical disease? We will continue this work with four specific aims: (1) What are the mechanisms of B-cell depletion as a potential therapy for SLE? (2) At what point in ontogeny can B cells lose tolerance? (3) How do CD4 T-cells influence the ontogeny of B cells? (4) Where are autoantibody forming cells found in SLE, particularly as regards the kidneys? The better understanding of the role of B cells in systemic autoimmunity and the therapeutic effects of B-cell depletion will permit the more efficient use of existent B-cell targeted therapies, such as rituximab, and the more rationale development of newer B- cell therapies or combinations of therapies. It is likely that new biomarkers will need to be identified to allow the rational monitoring of B-cell directed therapies and the appropriate selection of patients who are likely to respond. This project will use an experimental mouse model of the complex autoimmune disease systemic lupus erythematosus. The studies will particularly investigate the role of one of the key cells involved in this disorder: the B lymphocyte. The knowledge gained will improve of our understanding of the pathogenesis of systemic lupus erythematosus and how we can target the B lymphocytes in treatment.