Role and Mechanism of PDI-PDL Pathway in EAE

PDI-PDL通路在EAE中的作用和机制

• 批准号: 7154054
• 负责人: Samia J. Khoury
• 金额: $ 30.42万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154054
• 关键词: Acute; Acute Disease; Adoptive Transfer; Animal Model; Antigen-Presenting Cells; Antigens; Apoptosis; Astrocytes; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Biological Assay; Bone Marrow; Bone Marrow Cells; Brain; C57BL/6 Mouse; CD28 gene; CTLA4 gene; Cell Death; Cell Differentiation process; Cell physiology; Cells; Central Nervous System Diseases; Chimeric Proteins; Chronic; Chronic Disease; Clinical; Clinical Course of Disease; Clonal Expansion; Compatible; Complex; Cytokine Receptors; Data; Development; Disease; Disease Progression; Disease model; Effector Cell; Experimental Autoimmune Encephalomyelitis; Failure; Family; Goals; Homologous Gene; Immune response; Immunization; In Situ; In Vitro; Inflammatory; Investigation; Lead; Life; Ligands; Ligation; Lymphoid Cell; Mediating; Memory; Modeling; Monoclonal Antibodies; Mus; Myelin; Neuraxis; Organ; Pathology; Pathway interactions; Peptides; Peripheral; Phenotype; Physiological; Play; Principal Investigator; Production; Radiation Chimera; Reading; Reagent; Recurrent disease; Regulation; Regulatory Pathway; Relapse; Research Personnel; Role; Signal Transduction; Spinal Cord; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Th1 Cells; Time; To autoantigen; Transgenic Animals; Transgenic Organisms; Withdrawal; autoreactive T cell; cell mediated immune response; chemokine; clinically relevant; cytokine; desire; in vivo; knockout gene; nerve stem cell; novel therapeutics; programs; research study; response; tool

DESCRIPTION (provided by applicant): EAE is an inflammatory disease of the central nervous system initiated by myelin antigen-specific encephalitogenic CD4+ Th1 cells. After encountering antigen, T cells receive signal 1 through the TCR and signal 2 through "positive" costimulatory molecules leading to full activation. Other costimulatory molecules such as CTLA4 provide a negative signal for T cell activation and may be important for terminating immune responses. Recently, another pathway that provides negative signaling to T cells has been described, the PD1- PDL1/2 pathway. The main goal of this proposal is to define the functions and mechanisms of the PD1 pathway in regulating EAE. We have unique reagents (monoclonal antibodies and fusion proteins) and animal models (gene knockout and TCR transgenic animals) that will enable us to dissect the role of this pathway in a clinically relevant disease model. We will use these tools to study the following: Aim 1: What is the function of PD1-PDL pathway in regulating EAE in vivo? Our hypothesis is that the PD1-PDL1/PDL2 pathway negatively regulates autoimmune responses in vivo. Using blocking monoclonal antibodies as tools to investigate the functions and of this new pathway in autoimmune responses in acute and chronic EAE, and in relapsing disease. We will define the role of this pathway in regulating autoreactive T cells in vivo. We will also study the functions of this new pathway in active disease and passively induced disease. Aim 2: Role of PD 1- PDL1 in tolerance to autoantigens. Our hypothesis is that signaling through PD1 promotes tolerance in autoreactive T cells. We will use a signaling fusion protein targeting PDL1 to induce tolerance in EAE. We will use unique in vitro and in vivo assays including MOG TCR transgenic animals to better understand the mechanisms of targeting the PD1 costimulatory pathway in vivo. PDL1 and PDL2, are expressed on both professional bone marrow derived antigen-presenting cells and on parenchymal cells, by using PD1, PDL1, and PDL2 deficient mice we will investigate the role of parenchymal versus lymphoid cell expression of the ligands on the function of this pathway in regulating autoimmune responses. Aim 3: Interactions between PD1-PDL1/PDL2 pathway and other "positive" and "negative" regulatory pathways. Our hypothesis is that PD1-PDL pathway plays an important role in regulating EAE particularly in the absence of CD28. We will define the interactions between the PD1 pathway and other CD28 homologues (CD28, CTLA4, ICOS) in regulating EAE.

描述（申请人提供）：EAE是一种由髓磷脂抗原特异性致脑炎CD4+Th1细胞引发的中枢神经系统炎症性疾病。遇到抗原后，T 细胞通过 TCR 接收信号 1，通过“阳性”共刺激分子接收信号 2，从而实现完全激活。其他共刺激分子（例如 CTLA4）为 T 细胞激活提供负信号，并且可能对于终止免疫反应很重要。最近，另一种向 T 细胞提供负信号传导的途径已被描述，即 PD1-PDL1/2 途径。该提案的主要目标是明确PD1通路在调节EAE中的功能和机制。我们拥有独特的试剂（单克隆抗体和融合蛋白）和动物模型（基因敲除和 TCR 转基因动物），使我们能够剖析该通路在临床相关疾病模型中的作用。我们将使用这些工具来研究以下内容： 目标1：PD1-PDL 通路在体内调节 EAE 中的功能是什么？我们的假设是 PD1-PDL1/PDL2 通路负向调节体内自身免疫反应。使用阻断单克隆抗体作为工具来研究这种新途径在急性和慢性 EAE 以及复发性疾病中自身免疫反应中的功能和作用。我们将定义该途径在体内调节自身反应性 T 细胞中的作用。我们还将研究这一新途径在主动疾病和被动诱发疾病中的功能。目标 2：PD 1- PDL1 在自身抗原耐受中的作用。我们的假设是，通过 PD1 的信号传导可促进自身反应性 T 细胞的耐受性。我们将使用靶向 PDL1 的信号融合蛋白来诱导 EAE 耐受。我们将使用独特的体外和体内测定（包括 MOG TCR 转基因动物）来更好地了解体内靶向 PD1 共刺激途径的机制。 PDL1 和 PDL2 在专业骨髓来源的抗原呈递细胞和实质细胞上表达，通过使用 PD1、PDL1 和 PDL2 缺陷小鼠，我们将研究配体的实质与淋巴细胞表达对其功能的作用调节自身免疫反应的途径。目标 3：PD1-PDL1/PDL2 通路与其他“正”和“负”调节通路之间的相互作用。我们的假设是 PD1-PDL 通路在调节 EAE 中发挥重要作用，特别是在 CD28 缺失的情况下。我们将定义 PD1 通路与其他 CD28 同源物（CD28、CTLA4、ICOS）在调节 EAE 方面的相互作用。

项目成果

Plasticity of Ly-6C(hi) myeloid cells in T cell regulation.

Ly-6C(hi) 骨髓细胞在 T 细胞调节中的可塑性。

• 发表时间: 2011-09-01
• 作者: Zhu, Bing;Kennedy, Jennifer K;Wang, Yue;Sandoval;Cao, Li;Xiao, Sheng;Wu, Chuan;Elyaman, Wassim;Khoury, Samia J
• 通讯作者: Khoury, Samia J

Notch ligand delta-like 4 blockade alleviates experimental autoimmune encephalomyelitis by promoting regulatory T cell development.

Notch 配体 δ 样 4 阻断通过促进调节性 T 细胞发育来缓解实验性自身免疫性脑脊髓炎。

• 发表时间: 2011-09-01
• 作者: Bassil, Ribal;Zhu, Bing;Lahoud, Youmna;Riella, Leonardo V;Yagita, Hideo;Elyaman, Wassim;Khoury, Samia J
• 通讯作者: Khoury, Samia J

Notch receptors and Smad3 signaling cooperate in the induction of interleukin-9-producing T cells.

Notch 受体和 Smad3 信号传导协同诱导产生白细胞介素 9 的 T 细胞。

• 发表时间: 2012-04-20
• 影响因子: 32.4
• 作者: Elyaman, Wassim;Bassil, Ribal;Bradshaw, Elizabeth M;Orent, William;Lahoud, Youmna;Zhu, Bing;Radtke, Freddy;Yagita, Hideo;Khoury, Samia J
• 通讯作者: Khoury, Samia J

Subventricular zone microglia transcriptional networks.

室下区小胶质细胞转录网络。

• 发表时间: 2011-07
• 作者: Starossom, Sarah C;Imitola, Jaime;Wang, Yue;Cao, Li;Khoury, Samia J
• 通讯作者: Khoury, Samia J

IL-4 and retinoic acid synergistically induce regulatory dendritic cells expressing Aldh1a2.

IL-4 和视黄酸协同诱导表达 Aldh1a2 的调节性树突状细胞。

• 发表时间: 2013-09-15
• 作者: Zhu, Bing;Buttrick, Thomas;Bassil, Ribal;Zhu, Chen;Olah, Marta;Wu, Chuan;Xiao, Sheng;Orent, William;Elyaman, Wassim;Khoury, Samia J
• 通讯作者: Khoury, Samia J