Competition Among Pathogenic or Protective T Cell Clones

致病性或保护性 T 细胞克隆之间的竞争

• 批准号: 6726358
• 负责人: ELI E SERCARZ
• 金额: $ 10.24万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6726358
• 关键词: Leishmania; T cell receptor; T lymphocyte; autoimmune disorder; cell adhesion; cell cell interaction; clone cells; communicable diseases; confocal scanning microscopy; cytotoxicity; enzyme linked immunosorbent assay; experimental allergic encephalomyelitis; flow cytometry; genetically modified animals; helper T lymphocyte; immunomagnetic separation; interleukin 12; laboratory mouse; major histocompatibility complex; myelin basic proteins; polymerase chain reaction

DESCRIPTION (provided by applicant): In this application, we will try to achieve knowledge of the types of competitive interactions that occur in autoimmune and in infectious situations, both with unprimed naive populations and with primed memory cells. There are many elements involved in establishing repertoire choice, at the MHC and at the T cell levels. From an enormous repertoire of potential players, very often a small group of clones with characteristics that enhance disease emerge as "drivers" of the disease process. Often, such driver clones repeatedly occur in most individuals of the genetically restricted population. We would like to understand how such cells gain a competitive advantage. In the autoimmune encephalomyelitis (EAE) model of the B10.PL H-2u mouse, there are three transgenic lines of mouse all specific for the dominant determinant Acl-9 at the amino terminus of myelin basic protein. These transgenic cells will be followed for their early appearance, migratory properties, changing pattern of memory and adhesion surface markers, and cytokine/chemokine production and receptor patterns throughout the disease course. Are the drivers of autoimmunity always Th1 cells, always public, and of high affinity? The three clones will then be placed in competitive situations and we will ask under which conditions an advantage is gained by one of them. Does this advantage occur at the very outset of binding to the antigen-presenting cell? Or during the early days of neonatal (lymphopenic) life? What evidence is there for in vivo clonal competition? In these studies, CDR3-length polymorphism will be used to follow the unique structures of these clonal receptors, and ELISA spot analysis as well as CFSE tracing of division, and confocal imaging of specific cluster formation will serve to study the competitive interactions. In the infectious disease world, the driver of disease, again found in many individuals, is more often than not, a Th2 cell, preventing the development of a successful defense. In the leishmanial system which we are studying, we plan to skew the response with adenovirus vectors containing cytokine genes, so that previously susceptible animals such as the BALB/c, treated with IL-12-bearing-adenovirus, now becomes resistant, and now we will explore the probability of defining a protective (set of) clone(s) in this mouse. Such protective clones could be compared to those found in the initially resistant B10.D2. Likewise, we will study the dominant determinant in the Leishmania homologue of mammalian RACK (=LACK) and its variants to examine the nature of pathogenic Th2 driver clones. In each of the opposite disease models of autoimmunity and infectious disease, it is of great interest that the defense of the body might also be under the control of a particularly predominant clonal population.

描述（由申请人提供）：在本申请中，我们将尝试获得在自身免疫和感染情况下发生的竞争相互作用类型的知识，包括未启动的幼稚群体和启动的记忆细胞。在MHC和T细胞水平上，有许多因素涉及到建立保留库选择。在大量潜在参与者中，往往有一小群具有增强疾病特征的克隆体成为疾病进程的“驱动者”。通常，这样的驱动克隆反复发生在遗传受限群体的大多数个体中。我们想了解这些细胞是如何获得竞争优势的。在B10.PL H-2u小鼠自身免疫性脑脊髓炎（EAE）模型中，有3个转基因小鼠系均对髓鞘碱性蛋白氨基端显性决定因子Acl-9特异。这些转基因细胞的早期外观、迁移特性、记忆和粘附表面标记物的变化模式、细胞因子/趋化因子的产生和受体在整个疾病过程中的模式将被跟踪。自身免疫的驱动因子总是Th1细胞，总是公共的和高亲和力的吗？然后，这三个克隆体将被置于竞争环境中，我们将询问在何种条件下其中一个会获得优势。这种优势在与抗原呈递细胞结合的一开始就出现了吗？或者在新生儿（淋巴细胞减少）生命的早期？活体克隆竞争有什么证据？在这些研究中，cdr3长度多态性将用于跟踪这些克隆受体的独特结构，ELISA斑点分析和CFSE分裂追踪以及特定簇形成的共聚焦成像将用于研究竞争相互作用。在传染病的世界里，疾病的驱动者，同样在许多个体中发现，往往是Th2细胞，阻止了成功防御的发展。在我们正在研究的利什曼系统中，我们计划用含有细胞因子基因的腺病毒载体来扭曲反应，这样以前易感的动物，如BALB/c，用携带il -12的腺病毒治疗，现在变得耐药，现在我们将探索在该小鼠中定义保护性（一组）克隆的可能性。这种保护性克隆可以与最初具有抗性的B10.D2中发现的克隆相比较。同样，我们将研究哺乳动物RACK的利什曼原虫同源物（=LACK）及其变体中的显性决定因素，以检验致病性Th2驱动克隆的性质。在自身免疫和传染性疾病的每一种相反的疾病模型中，人体的防御也可能在一个特别占优势的克隆群体的控制下，这是非常有趣的。