MEMORY T CELLS IN EAE

EAE 中的记忆 T 细胞

• 批准号: 7387035
• 负责人: Samia J. Khoury
• 金额: $ 39.53万
• 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: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7387035
• 关键词: Acute; Address; Animal Model; Animals; Antigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Blocking Antibodies; CD8B1 gene; CTLA4 gene; Cell Death; Cells; Central Nervous System Diseases; Chimeric Proteins; Chronic Disease; Clinical; Clonal Expansion; Collaborations; Data; Development; Disease; Disease model; Effector Cell; Experimental Autoimmune Encephalomyelitis; Family; Funding; Gene Targeting; Generations; Goals; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunoglobulins; Immunologic Memory; Immunotherapy; In Vitro; Inflammation; Inflammatory; Investigation; Mediating; Memory; Modeling; Mucin 1 protein; Mucins; Multiple Sclerosis; Mus; Neuraxis; Organ; Outcome; Pathogenesis; Pathology; Pathway interactions; Pattern; Peripheral; Play; Population; Predisposition; Process; Proteins; Receptor Signaling; Recurrent disease; Regulation; Relapse; Reporter; Resistance; Rodent; Role; Signal Transduction; Societies; Spleen; Stimulus; T memory cell; T-Cell Receptor; T-Lymphocyte; TNFSF4 gene; Th2 Cells; Vaccination; Virus Diseases; Withdrawal; cell mediated immune response; cytokine; design; desire; disease characteristic; disease phenotype; human disease; in vivo; lymph nodes; memory CD4 T lymphocyte; migration; novel; novel strategies; tool

DESCRIPTION (provided by applicant): An important recently recognized barrier to induction of immunologic tolerance in humans is the fact that the adaptive immune response, by virtue of evolutionary design, is destined to generate immunologic memory; and initial data suggest that memory T cells tend to be resistant to induction of tolerance. EAE is an inflammatory disease of the central nervous system that mimics certain aspects of MS. We have established a new model of EAE that is mediated by antigen-specific memory T cells that is distinct from disease mediated by effector T cells. The major goal of this project is to investigate the role of memory T cells EAE, and to investigate their susceptibility to tolerance strategies in vivo. Aim1: We will investigate the characteristics of disease mediated by memory versus effector T cells, including clinical features, central nervous system (CNS) pathology, and peripheral immune responses. Aim 2: Our hypothesis is that autoreactive memory T cells can be activated by nonspecific immune stimuli (viral infection, inflammation, vaccination) leading to reactivation/progression of clinical disease. In this aim we will investigate which stimuli can activate autoreactive memory T cells in vivo and define the clinical and pathological disease pattern mediated by these cells and the mechanisms of how this happens. Aim 3: Our hypothesis is that autoreactive memory T cells are less dependent on conventional (CD28) T cell costimulatory pathways for activation and require distinct and unique T cell costimulatory signals for full activation, differentiation and survival in vivo. These cosimulatory pathways include ICOS-B7h and CD134-CD143L. Using blocking antibodies against B7h and CD134L, we will investigate the functions and mechanisms of these pathways in regulating autoimmune disease mediated by memory T cells in vivo.

描述（由申请人提供）：最近认识到的在人类中诱导免疫耐受的一个重要障碍是这样一个事实，即适应性免疫反应通过进化设计注定会产生免疫记忆；初步数据表明，记忆 T 细胞往往对诱导耐受具有抵抗力。 EAE 是一种中枢神经系统炎症性疾病，与 MS 的某些方面相似。我们建立了一种新的 EAE 模型，该模型由抗原特异性记忆 T 细胞介导，与效应 T 细胞介导的疾病不同。该项目的主要目标是研究记忆 T 细胞 EAE 的作用，并研究它们对体内耐受策略的敏感性。目标1：我们将研究记忆与效应T细胞介导的疾病的特征，包括临床特征、中枢神经系统（CNS）病理学和外周免疫反应。目标 2：我们的假设是，非特异性免疫刺激（病毒感染、炎症、疫苗接种）可以激活自身反应性记忆 T 细胞，从而导致临床疾病的重新激活/进展。为此，我们将研究哪些刺激可以在体内激活自身反应性记忆 T 细胞，并定义这些细胞介导的临床和病理疾病模式以及其发生的机制。目标 3：我们的假设是，自身反应性记忆 T 细胞较少依赖于传统 (CD28) T 细胞共刺激途径的激活，并且需要独特且独特的 T 细胞共刺激信号才能在体内完全激活、分化和存活。这些共模拟途径包括 ICOS-B7h 和 CD134-CD143L。使用针对 B7h 和 CD134L 的封闭抗体，我们将研究这些途径在调节体内记忆 T 细胞介导的自身免疫性疾病中的功能和机制。