Experimental Induction of SLE by Altered Ia

改变 Ia 诱导 SLE 的实验

• 批准号: 8099751
• 负责人: ROBERT A. EISENBERG
• 金额: $ 32.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099751
• 关键词: Address; Anatomy; Area; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Biological Markers; C57BL/6 Mouse; CD22 gene; CD4 Positive T Lymphocytes; Cell Therapy; Cells; Chronic; Clinical; Combined Modality Therapy; Complex; Data; Development; Disease; Growth; Human; Inbred Mouse; Interleukin-4; Kidney; Knowledge; Lymphoid; MHC Class II Genes; MS4A1 gene; Mature B-Lymphocyte; Measurement; Modeling; Monitor; Mus; Pathogenesis; Patient Selection; Phenotype; Play; Population; Process; Production; Resistance; Role; Signal Transduction; Specificity; Spleen; System; Systemic Lupus Erythematosus; T-Lymphocyte; Therapeutic; Therapeutic Effect; Time; Transgenic Organisms; Variant; Work; autoreactive B cell; autoreactivity; graft vs host reaction; improved; kidney cell; mouse model; receptor; response; rituximab

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.

描述（由申请人提供）：B细胞公差的丧失对于SLE自身免疫的发病机理至关重要。为了探测此过程中涉及的机制，我们利用各种受摄取的转基因变种，利用了SLE的慢性移植与SLE的宿主模型与SLE的宿主模型，在该模型中，我们将MHC II类不兼容的BM12脾细胞或纯化的CD4脾T细胞转移到C57BL/6小鼠中。该系统使我们能够详细研究以SLE为特征的B细胞耐受性丧失的机理。我们以前在该项目的工作以及我们最近的初步数据已经确定了我们在当前应用程序中提出的几个令人兴奋的方向。我们将解决以下问题：为什么SLE会使B细胞抗MAB抗耗尽的B细胞？受体编辑和推理包含在B细胞耐受性的丧失中起什么作用？ CD4 T细胞如何控制B细胞的个体发育，从而可以对同种异体T细胞反应？自身抗体形成细胞的表型和分布是什么，与临床疾病有何关系？我们将以四个特定的目的继续这项工作：（1）B细胞耗竭作为SLE的潜在疗法的机制是什么？ （2）B细胞在个体发育的什么时候会失去耐受性？ （3）CD4 T细胞如何影响B细胞的个体发育？ （4）在SLE中发现自身抗体在哪里形成细胞，尤其是在肾脏方面？ 对B细胞在全身自身免疫性和B细胞耗竭的治疗作用中的作用的更好理解将使现有的B细胞靶向疗法（例如利妥昔单抗）更有效地使用，以及更新的B-细胞疗法或疗法组合的基本原理发展。可能需要确定新的生物标志物，以允许对B细胞的定向疗法进行合理监测，并适当选择可能反应的患者。该项目将使用复杂自身免疫性疾病全身性红斑狼疮的实验小鼠模型。研究将特别研究该疾病中涉及的关键细胞之一的作用：B淋巴细胞。获得的知识将改善我们对系统性红斑狼疮的发病机理的理解，以及我们如何靶向治疗中的B淋巴细胞。