Role of B7 costimulation in induction and regulation of EAE

B7 共刺激在 EAE 诱导和调节中的作用

• 批准号: 7555387
• 负责人: VIJAY K. KUCHROO
• 金额: $ 41.23万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555387
• 关键词: Accounting; Address; Age; Animal Model; Antibodies; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Asians; Attention; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Cell Activation; B-Lymphocytes; Breeding; CD28 gene; CD4 Positive T Lymphocytes; CD80 gene; CNS autoimmunity; Cell Differentiation process; Cells; Clinical; Collaborations; Data; Development; Disease; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Family; Foundations; Generations; Genes; Goals; Grant; Human; Immune response; In Vitro; Inflammatory; Injury; Interferons; Interleukin-17; Knock-in Mouse; Lead; Lesion; Mediating; Methods; Modeling; Molecular; Monoclonal Antibodies; Mouse Strains; Multiple Sclerosis; Mus; Myelin; Neuraxis; Neuromyelitis Optica; Optic Nerve; Optic Neuritis; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Phase; Play; Population; Production; Proteins; Receptors, Antigen, B-Cell; Regulation; Relative (related person); Role; Self Tolerance; Severities; Signal Transduction; Spinal Cord; Structure of germinal center of lymph node; T-Cell Activation; T-Cell Activation Pathway; T-Lymphocyte; Testing; Th1 Cells; Th2 Cells; Therapeutic; Tissues; Transgenic Mice; Up-Regulation; base; central nervous system demyelinating disorder; clinical phenotype; human disease; in vivo; insight; interest; prevent; receptor; response; tool

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is a T cell mediated autoimmune disease that serves as an animal model of Multiple Sclerosis (MS). We have previously generated a MOG TcR (2D2) transgenic mouse which, when crossed onto a MOG B cell knock-in TH mouse, develop an accelerated, severe disease with inflammatory lesions distributed preferentially in the optic nerve and spinal cord, typical of neuromyelitis optica or Devic's disease observed in human MS. The mechanisms by which autopathogenic T and B cells collaborate to induce such severe disease in the 2D2 x TH mice are not known. Signaling via the B7:CD28/CTLA4 costimulatory pathway can provide a potent costimulatory signal for T and B cell activation, but other pathways like ICOS:ICOSL and TIM-1:Tim-1L pathways also play important roles in CD4+ T cell activation, differentiation, and effector function. The overall goal of this project is to define the role of these 3 different costimulatory pathways, B7:CD28/CTLA4, ICOS-ICOSL and Tim-1:Tim1L pathway in the activation of pathogenic T and B cells in the development of Devic's disease in 2D2 x TH mice. Our hypothesis is that, whereas the B7:CD28/CTLA4 pathway plays a crucial role in the induction and effector functions of the autopathogenic T cells, ICOS and TIM-1 pathways also play important roles in T:B cell collaboration and generation of pathogenic effector T and B cells. The 2D2 x TH mice that develop spontaneous Devic's disease provide us a unique opportunity to study the role of costimulatory pathways in the generation of Devic's disease. To address these issues, we have proposed the following specific aims: 1: Characterize the MOG TcR and MOG B cell "knock-in" mice for their ability to induce clinical Devic's-like disease and T:B cell collaboration. Since the mice develop spontaneous disease, we will determine when and where the T and B cells are activated, what is the role of B cells in antigen presentation and what is the molecular basis for the induction of Devic's disease; 2: Compare the roles of the CD28 and ICOS costimulatory pathways in the generation of pathogenic B and T cells and induction of Devic's like disease in the 2D2xTH mice. We will examine the role of B7-1/B7-2 and ICOSL in the activation of B cells as APCs and generation of T cell dependent antibody production, and test their effect on the induction of Devic's disease when crossed to the 2D2 x TH mice; 3: Study the relationships among the CD28, ICOS and TIM-1 costimulatory pathways in the induction and effector phases of EAE. We will test the effect of loss of ICOS and CD28 on the expression of Tim-1, test whether anti-Tim-1 antibody preferentially generates pathogenic effector T cells and inhibits functions of regulatory T cells, and whether loss of Tim-1 will inhibit Devic's disease in the 2D2 x TH mice when bred with Tim-1-/- mice. Taken together, these studies should provide clear answers, enabling us to define mechanisms by which these costimulatory pathways influence the development pathogenic T and B cell effectors and in regulating T:B cell collaboration and development of Devic's disease. Project Narrative: The overall goal of this project is to study the roles of the costimulatory pathways (B7:CD28/CTLA4, ICOS:ICOSL and TIM-1:TIM-1L) in T:B collaboration and in inducing autopathogenic T and B cell responses. This will be undertaken by using MOG TcR transgenic mice that co-express MOG specific B cell receptors and develop fulminant autoimmunity of the CNS spontaneously similar to human Devic's disease. The effect of each of the three costimulatory pathways on the development of the disease will be analyzed.

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）是T细胞介导的自身免疫性疾病，可作为多发性硬化症（MS）的动物模型。我们先前已经产生了一种MOG TCR（2d2）转基因小鼠，该小鼠在Mog B细胞敲入小鼠TH小鼠上时，会出现一种加速的，严重的疾病，炎症性病变优先分布在视神经和脊髓中，这是典型的神经素炎或devicic在人类MS中观察到的神经肌炎或Devic。尚不清楚自杀性T和B细胞在2d2 x小鼠中诱导这种严重疾病的机制。通过B7：CD28/CTLA4加生途径传导可以为T和B细胞激活提供有效的共刺激信号，但是其他途径（例如ICOS：ICOSL和TIM-1：TIM-1L：TIM-1L途径）也在CD4+ T细胞激活，分化，差异，效果函数中也起着重要作用。该项目的总体目标是定义这三种不同的共刺激途径的作用，B7：CD28/CTLA4，ICOS-ICOSL和TIM-1：TIM1L途径在病原T和B细胞激活2D2 x小鼠中Devic病的发展中。我们的假设是，尽管B7：CD28/CTLA4途径在自抗致病性T细胞的诱导和效应子功能中起着至关重要的作用，ICOS和TIM-1途径在T：B细胞协作和致病性效应T和B细胞的产生中也起着重要作用。发展自发Devic的2d2 X小鼠为我们提供了一个独特的机会，可以研究共刺激途径在Devic氏病中的作用。为了解决这些问题，我们提出了以下特定目的：1：特征MOG TCR和MO​​G B细胞“敲入”小鼠的小鼠诱导临床Devic的疾病和T：B细胞协作的能力。由于小鼠发生了自发性疾病，我们将确定T和B细胞在何时何地激活T和B细胞，B细胞在抗原呈递中的作用是什么以及诱导Devic疾病的分子基础是什么？ 2：比较CD28和ICOS共刺激途径在致病性B和T细胞产生中的作用，以及在第22x小鼠中诱导Devic的疾病。我们将研究B7-1/B7-2和ICOSL在B细胞激活APC和T细胞依赖性抗体的产生中的作用，并测试其对Devic疾病诱导的影响，当时Devic的疾病的影响； 3：研究EAE的诱导和效应阶段中CD28，ICOS和TIM-1共刺激途径之间的关系。我们将测试ICOS和CD28丢失对TIM-1的表达的影响，测试抗TIM-1抗体是否优先生成致病效应T细胞并抑制调节性T细胞的功能，以及tim-1的丧失是否会抑制与tim-1-1-/ - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - / - /-1-/ - / - / - / - / - / - / - / - / - / - / - 小鼠。综上所述，这些研究应提供明确的答案，从而使我们能够定义这些共刺激途径影响发育致病性T和B细胞效应子的机制，并在调节T：B细胞的协作和Devic疾病的开发方面。项目叙述：该项目的总体目标是研究costimunation途径（B7：CD28/CTLA4，ICOS：ICOSL：ICOSL和TIM-1：TIM-1L）在T：B协作以及诱导自动性T和B细胞反应中的作用。这将通过使用MOG TCR转基因小鼠来表达MOG特异性B细胞受体，并发展与人类Devic氏病自发的CNS的暴发自身免疫性。将分析三种共刺激途径对疾病发展的影响。