Role of B7H4 and CD48 in EAE

B7H4 和 CD48 在 EAE 中的作用

• 批准号: 7568196
• 负责人: Arlene H. Sharpe
• 金额: $ 45.54万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568196
• 关键词: Address; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; CD58 Antigens; Disease susceptibility; Experimental Autoimmune Encephalomyelitis; Family member; Genetic; Goals; Homologous Gene; Human; Insulin-Dependent Diabetes Mellitus; Lead; Mediating; Multiple Sclerosis; Mus; Numbers; Organ; Phase; Process; Role; Signal Transduction; T-Cell Activation; T-Lymphocyte; Tissues; Transgenic Mice; Upper arm; in vivo; insight; migration; novel; response; tool

The overall goal is to dissect the functional roles of the recently identified B7 family member, B7-H4, and the SLAM family member, CD48 (a CD2 ligand), in regulating organ-specific autoimmune diseases. This focus is driven by recent genetic studies of Multiple Sclerosis and murine type 1 diabetes that have implicated the genetic locus that contains these costimulatory molecules (human or mouse homologues) with disease susceptibility, together with our recent studies that point to important roles for B7-H4 and CD48 in regulating T cell activation and tolerance. To investigate the roles of B7-H4 and CD48-mediated signals in the afferent arm of the response where T cells become activated in the periphery, and in the effector arm, where potentially pathogenic T cells are driven to mediate tissue destruction, we are proposing a multifaceted approach. We will 1)investigate the role of the B7-H4 in regulating T cell tolerance and autoimmunity; 2)analyze the role of CD48 in regulating the induction and effector phases of EAE; and 3)examine the roles of CD48 and B7-H4 in regulating T and B cell tolerance. We have assembled a number of novel tools that will enable us to address these important issues. To dissect the role of B7-H4 in EAE, we have developed B7-H4lg and anti-B7-H4 mAb. We also have available B7-H4-/- mice and are in the process of generating transgenic mice that inducibly express B7-H4. Our CD48-/- mice, and anti-CD48 mAb will serve as definitive tools for examining the role of CD48 during EAE. We will use MOG 35-55 specific TCR transgenic mice to visualize the effects of B7-H4 and CD48 dysregulation on the activation, migration and expansion of naive and activated T cells in vivo, and MOG 35-55 TCR x Th double transgenic mice to analyze the roles of B7-H4 and CD48 in regulating B and T cell tolerance to MOG. Taken together, these studies should lead to insights into how B7-H4 and CD48 costimulatory regulate the responses of self-reactive T cells.

总体目标是剖析最近鉴定的B7家族成员B7-H4和SLAM家族成员CD 48（一种CD 2配体）在调节器官特异性免疫应答中的功能作用。 自身免疫性疾病这一焦点是由最近对多发性硬化症和小鼠1型糖尿病的遗传研究所驱动的，这些研究涉及含有这些具有疾病易感性的共刺激分子（人或小鼠同源物）的遗传基因座，以及我们最近的研究，这些研究指出B7-H4和CD 48在调节T细胞活化和免疫调节中的重要作用。 宽容为了研究B7-H4和CD 48介导的信号在反应的传入臂中的作用，其中T细胞在外周中被激活，并且在效应臂中，潜在的致病性T细胞被驱动以介导组织破坏，我们提出了一种多方面的方法。我们将1）研究B7-H4在调节T细胞耐受和自身免疫中的作用; 2）分析CD 48在调节EAE的诱导期和效应期中的作用;和3）检查CD 48和B7-H4在调节T和B细胞耐受中的作用。我们已经收集了一些新的工具，使我们能够解决这些重要问题。为了分析B7-H4在EAE中的作用，我们开发了B7-H4 lg和抗B7-H4 mAb。我们也 有可用的B7-H4-/-小鼠，并且正在产生可诱导表达B7-H4的转基因小鼠。我们的CD 48-/-小鼠和抗CD 48 mAb将作为确定性工具，用于检查CD 48在EAE期间的作用。我们将使用MOG 35-55特异性TCR转基因小鼠来可视化 B7-H4和CD 48失调对体内初始和活化T细胞的活化、迁移和扩增的影响，以及MOG 35-55 TCR x Th双转基因小鼠，以分析B7-H4和CD 48在调节B和T细胞对MOG耐受中的作用。综上所述，这些研究应该有助于深入了解B7-H4和CD 48共刺激如何调节自身反应性T细胞的反应。