ANTISM B CELL REGULATION

抗 B 细胞调节

• 批准号: 2686728
• 负责人: Stephen H Clarke
• 金额: $ 21.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2686728
• 关键词: B lymphocyte; CD antigens; CD95 molecule; T lymphocyte; antibody formation; antinuclear autoantibody; cell cell interaction; genetically modified animals; immune tolerance /unresponsiveness; laboratory mouse; leukocyte activation /transformation; transfection

DESCRIPTION (Adapted from Investigator's abstract): The principal objective of this investigator is to understand the regulation of anti-Sm and anti-single stranded (ss) DNA B-cells in normal mice, and to identify the stage at which tolerance to these antigens is lost in autoimmune mice. Responses to Sm and ssDNA are characteristic of human SLE and MRL/Mp-lpr/lpr (MRL/lpr) mice that spontaneously develop an SLE-like disease. We have generated Ig H chain Transgenic (Tg) mice using a H chain gene rearrangement that encodes antibodies specific for Sm and ssDNA. These mice develop large numbers of splenic anti-Sm and anti-ssDNA B-cells, but do not spontaneously secrete autoantibody. Thus, they are regulated in the periphery, but the mechanism appears to be different from any so-far described. The investigator proposes that these cells are eliminated at a late stage in B-cell differentiation, during the transition from an immature B-cell to a mature B-cell. In Aim 1, he will test predictions of this hypothesis using double Tg mice in which every B-cell has the same specificity and affinity for Sm. Functional anti-Sm T-cells are present in these Ig Tg mice, and therefore in Aim 2 he will determine whether exclusion is Fas dependent and T-cell mediated. In the third aim, he will test the hypothesis that the strength of the tolerogenic signal is affected by the response modulators CD19 and CD22. This will be accomplished by altering the availability of these proteins by crossing the anti-Sm Tg mice with CD19 Tg and CD22 knockout mice. In the fourth aim, he will use retroviral gene transfer to introduce the SmD gene in mouse bone marrow to test the hypothesis that the defect in B-cell tolerance in MRL/lpr mice is manifest only in exclusion from the mature B-cell subset, not in other forms of B-cell tolerance, central deletion or anergy. He will induce central deletion of anti-Sm B-cells in MRL/lpr mice and determine whether this blocks the spontaneous development of the anti-Sm response.

描述（改编自研究者的摘要）：主要目标 本研究者的目的是了解抗 Sm 的调节和 正常小鼠体内的抗单链 (ss) DNA B 细胞，并鉴定 自身免疫小鼠对这些抗原的耐受性丧失的阶段。 对 Sm 和 ssDNA 的反应是人类 SLE 和 MRL/Mp-lpr/lpr 的特征 (MRL/lpr) 小鼠自发患上 SLE 样疾病。 我们有 使用 H 链基因重排生成 Ig H 链转基因 (Tg) 小鼠 编码 Sm 和 ssDNA 特异性抗体。 这些老鼠发育得很大 脾脏抗 Sm 和抗 ssDNA B 细胞的数量，但不会自发地 分泌自身抗体。 因此，它们在外围受到监管，但 机制似乎与迄今为止所描述的任何机制都不同。 这 研究人员提出，这些细胞在晚期阶段被消除 B 细胞分化，从未成熟 B 细胞转变为成熟 B 细胞的过程 成熟的 B 细胞。 在目标 1 中，他将使用以下方法测试该假设的预测： 双 Tg 小鼠，其中每个 B 细胞都具有相同的特异性和亲和力 对于SM。这些 Ig Tg 小鼠体内存在功能性抗 Sm T 细胞，并且 因此，在目标 2 中，他将确定排除是否依赖于 Fas，并且 T细胞介导。 在第三个目标中，他将检验以下假设： 耐受信号的强度受到反应调节剂的影响 CD19 和 CD22。 这将通过改变可用性来实现 通过将抗 Sm Tg 小鼠与 CD19 Tg 和 CD22 杂交来获得这些蛋白质 基因敲除小鼠。 在第四个目标中，他将利用逆转录病毒基因转移 将SmD基因引入小鼠骨髓中以检验以下假设： MRL/lpr 小鼠 B 细胞耐受性缺陷仅在排除时表现出来 来自成熟的 B 细胞亚群，而不是其他形式的 B 细胞耐受性， 中枢缺失或无能。 他将诱导抗Sm的中心删除 MRL/lpr 小鼠中的 B 细胞，并确定这是否会阻止自发性 抗Sm反应的发展。