ANTISM B CELL REGULATION

抗 B 细胞调节

• 批准号: 6170977
• 负责人: Stephen H Clarke
• 金额: $ 23.11万
• 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/6170977
• 关键词: B lymphocyte; CD19 molecule; CD22 molecule; 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（改编自研究者摘要）：主要目的 本研究的目的是了解抗Sm的调节， 抗单链（ss）DNA B细胞在正常小鼠，并确定 在自身免疫小鼠中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）小鼠自发地发展SLE样疾病。 我们有 使用H链基因重排产生的IG H链转基因（Tg）小鼠 编码Sm和ssDNA特异性抗体。 这些老鼠长得很大 脾抗Sm和抗ssDNA B细胞的数量，但不自发 分泌自身抗体。 因此，他们在外围受到管制，但 这一机制似乎与迄今为止所描述的任何机制都不同。 的 研究人员认为，这些细胞是在晚期被消除的， B细胞分化，在从未成熟的B细胞到成熟的B细胞的过渡期间， 成熟B细胞 在目标1中，他将使用 其中每个B细胞具有相同的特异性和亲和力的双Tg小鼠 对于Sm.功能性抗Sm T细胞存在于这些IG Tg小鼠中， 因此，在目标2中，他将确定排除是否依赖于Fas， T细胞介导的。 在第三个目标中，他将检验这样的假设： 致耐受性信号的强度受应答调节剂的影响 CD 19和CD 22。 这将通过改变 通过将抗Sm Tg小鼠与CD 19 Tg和CD 22 敲除小鼠 在第四个目标中，他将使用逆转录病毒基因转移， 在小鼠骨髓中引入SmD基因，以检验 MRL/lpr小鼠中B细胞耐受性的缺陷仅表现为排斥 从成熟的B细胞亚群，而不是在其他形式的B细胞耐受性， 中心缺失或无反应性。 他将诱导抗Sm的中心缺失 MRL/lpr小鼠中的B细胞，并确定这是否阻断了自发性 抗Sm反应的发展。