Experimental Induction of SLE by Altered Ia

描述（由申请人提供）：b细胞耐受性的丧失是SLE自身免疫发病机制的核心。为了探究这一过程的机制，我们利用SLE的慢性移植物抗宿主模型，将MHC ii类不相容的bm12脾细胞或纯化的CD4脾T细胞转移到C57BL/6小鼠，利用各种受体转基因变体。该系统使我们能够详细研究SLE特征b细胞耐受性丧失的机制。我们之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几个令人兴奋的方向，我们建议在当前的应用中进行。我们将解决以下问题：为什么SLE使B细胞抵抗单克隆抗体的消耗？受体编辑和等位基因包涵在B细胞耐受性丧失中起什么作用？CD4 T细胞如何控制B细胞的个体发生，从而使它们能够对同种异体反应性T细胞作出反应？自身抗体形成细胞的表型和分布是什么？这与临床疾病有什么关系？我们将继续这项工作，有四个具体目标：(1)b细胞耗竭作为SLE潜在治疗的机制是什么？(2)在个体发生过程中，B细胞在什么时候失去耐受性？(3) CD4 t细胞如何影响B细胞的发生？(4)自身抗体形成细胞在SLE，尤其是肾脏中见于何处？

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.