Experimental Induction of SLE by Altered Ia

改变 Ia 诱导 SLE 的实验

• 批准号: 6789950
• 负责人: ROBERT A. EISENBERG
• 金额: $ 29.8万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6789950
• 关键词: B lymphocyte; MHC class II antigen; autoantibody; enzyme linked immunosorbent assay; gene expression; genetically modified animals; graft versus host disease; helper T lymphocyte; immune tolerance /unresponsiveness; immunoglobulins; immunomagnetic separation; laboratory mouse; phenotype; systemic lupus erythematosus

DESCRIPTION (provided by applicant): The autoimmune chronic graft-versus-host (cGVH) reaction in mice is a powerful model to investigate the mechanisms of loss of B-cell tolerance and the mechanisms whereby failure of such tolerance can lead to systemic autoimmunity characteristic of systemic lupus erythematosus (SLE). 1) Hypothesis: Different mechanisms of tolerance are important in regulating the anti-dsDNA response resulting from different Ig transgenes, cGVH will be induced in a series of immunoglobulin site-directed (knockin) transgenic mouse strains. 1) Hypothesis: The loss of tolerance in B cells in the cGVH model of SLE is accompanied by changes in gene expression that can be documented at the RNA level. Such genes and their protein products will be attractive targets for quantifying disease activity, understanding the molecular mechanisms that underlie the loss of B-cell tolerance and intervening therapeutically. 1) Hypothesis: The loss of tolerance in B cells in the cGVH model of SLE occurs because of the interaction of abnormal (allo-) T-cell help with B cells at discrete developmental stages. Transgenic B cells will be purified by surface markers of ontogeny and transferred in an adoptive cGVH system. 1) Hypothesis: The loss of tolerance in B cells in the cGVH model of SLE occurs in a small subpopulation, even in recipient mice with a highly skewed B-cell repertoire. This implies further failures of tolerance checkpoints, perhaps on a stochastic basis, that needs to be elucidated. 1) Hypothesis: Specific T cells from the recipient are critical for the cGVH autoimmune reaction. CD4 T cells permit autoreactive B cells to become receptive to allohelp by mechanisms to be explored. These studies will elucidate how a B cell with specificity for an important lupus specific antigen (dsDNA) can lose tolerance and become autoreactive. Since this process of tolerance loss is central to the pathogenesis of SLE, the results will help clarify some of the fundamental underlying mechanisms of this disease.

描述（由申请人提供）：小鼠自身免疫性慢性移植物抗宿主（cGVH）反应是一个强大的模型，可以研究b细胞耐受性丧失的机制，以及这种耐受性失败导致系统性红斑狼疮（SLE）系统性自身免疫特征的机制。