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: 6828690
• 负责人: ELI E SERCARZ
• 金额: $ 30.71万
• 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/6828690
• 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)：在这项提案中，我们将努力了解在自身免疫和感染情况下发生的竞争性相互作用的类型，包括与未启动的幼稚种群和启动的记忆细胞。在MHC和T细胞水平上，建立曲目选择涉及许多因素。从一个庞大的潜在玩家剧目中，往往有一小群具有增强疾病特征的克隆人出现，成为疾病过程的“驱动力”。通常，这样的驱动克隆在受遗传限制的人群中的大多数个体中重复出现。我们想了解这些细胞是如何获得竞争优势的。在B10.PL H-2U小鼠的自身免疫性脑脊髓炎(EAE)模型中，有3个转基因系均针对髓鞘碱性蛋白氨基末端的优势决定簇acl-9。这些转基因细胞将在整个疾病过程中因其早期出现、迁移特性、记忆和黏附表面标志物的变化模式以及细胞因子/趋化因子的产生和受体模式而受到关注。自身免疫的驱动者总是Th1细胞，总是公共的，并且具有高亲和力吗？然后这三个克隆人将被放在竞争的情况下，我们将询问他们中的一个在什么条件下获得优势。这种优势是在与抗原提呈细胞结合的一开始就出现的吗？还是在新生儿(淋巴细胞减少症)的早期？有什么证据表明体内克隆竞争？在这些研究中，CDR3长度多态将被用来跟踪这些克隆受体的独特结构，ELISA斑点分析以及分裂的CFSE追踪和特定簇形成的共聚焦成像将用于研究竞争相互作用。在传染病世界中，疾病的驱动力，也在许多人身上发现，往往是Th2细胞，阻止了成功的防御发展。在我们正在研究的利什曼系统中，我们计划倾斜含有细胞因子基因的腺病毒载体的反应，使以前易感的动物，如携带IL-12的腺病毒治疗的BALB/c，现在变得有耐药性，现在我们将探索在这个小鼠中定义一组保护性克隆(S)的可能性。这样的保护性克隆可以与最初抗病的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)及其变种利什曼原虫同源物中的主要决定因素，以检查致病Th2驱动克隆的性质。在自身免疫和传染病的每一种对立的疾病模型中，非常有趣的是，身体的防御可能受到一个特别占主导地位的克隆种群的控制。