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: 6891332
• 负责人: ELI E SERCARZ
• 金额: $ 40.95万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891332
• 关键词: Adenoviridae; Leishmania major; MHC class II antigen; T cell receptor; antigen presentation; autoimmunity; bacterial antigens; cell adhesion; cell cell interaction; cell differentiation; cell migration; communicable diseases; confocal scanning microscopy; cytokine; enzyme linked immunosorbent assay; experimental allergic encephalomyelitis; genetic polymorphism; genetically modified animals; helper T lymphocyte; immune response; laboratory mouse; leishmaniasis; ligands; protein biosynthesis; tissue /cell culture; transfection /expression vector

DESCRIPTION (provided by applicant): In this proposal, 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, CDR3-1ength polymorphism will be used to follow the unique structures of these clonal receptors, and ELISAspot 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 be under the control of a particularly predominant clonal population.

描述（由申请人提供）：在本提案中，我们将尝试获得在自身免疫和感染情况下发生的竞争性相互作用类型的知识，无论是与未引发的幼稚群体还是与引发的记忆细胞。在MHC和T细胞水平上，有许多元素参与建立库选择。在众多的潜在参与者中，往往会有一小群具有增强疾病特征的克隆人成为疾病过程的“驱动者”。通常，这种驱动克隆重复发生在遗传限制群体的大多数个体中。我们想了解这些细胞如何获得竞争优势。在B10.PL H-2u小鼠的自身免疫性脑脊髓炎（EAE）模型中，存在三种转基因小鼠品系，它们都对髓鞘碱性蛋白氨基末端的显性决定子Acl-9具有特异性。将跟踪这些转基因细胞的早期外观、迁移特性、记忆和粘附表面标志物的变化模式以及整个病程中细胞因子/趋化因子的产生和受体模式。自身免疫的驱动者是否总是Th 1细胞，总是公共的，高亲和力的？然后将这三个克隆体置于竞争的情况下，我们将询问在什么条件下其中一个获得优势。这种优势是否发生在与抗原呈递细胞结合的最初阶段？还是在新生儿（淋巴细胞减少）的早期？体内克隆竞争的证据是什么？在这些研究中，CDR 3 - 1长度多态性将用于跟踪这些克隆受体的独特结构，ELISAspot分析以及CFSE分裂追踪，以及特异性簇形成的共聚焦成像将用于研究竞争性相互作用。在传染病领域，疾病的驱动因素，再次在许多个体中发现，通常是Th 2细胞，阻止了成功防御的发展。在我们正在研究的利什曼原虫系统中，我们计划用含有细胞因子基因的腺病毒载体来改变反应，使得以前易感的动物如用携带IL-12的腺病毒治疗的BALB/c现在变得耐药，现在我们将探索在这种小鼠中定义保护性克隆的可能性。这种保护性克隆可以与在最初的抗性B10.D2中发现的那些进行比较。同样，我们将研究哺乳动物RACK（=LACK）及其变体的利什曼原虫同源物中的主导决定因素，以研究致病性Th 2驱动克隆的性质。在自身免疫和传染病的每一种相反的疾病模型中，身体的防御可能是在一个特别占优势的克隆种群的控制下，这是非常有趣的。