In vivo role of CTLA-4 in Costimulation and Autoimmunity

CTLA-4 在共刺激和自身免疫中的体内作用

• 批准号: 8071520
• 负责人: Arlene H. Sharpe
• 金额: $ 41.53万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071520
• 关键词: Address; Antibodies; Antigen-Presenting Cells; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; B7-DC antigen; Bone Marrow; CD28 gene; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chimera organism; Collaborations; Data; Dendritic Cells; Development; Diabetes Mellitus; Effector Cell; Equilibrium; Experimental Autoimmune Encephalomyelitis; Family; Family member; Frequencies; Funding; Generations; Goals; Grant; Hematopoietic; Human body; Immune system; Interleukin-6; Investigation; Knock-in Mouse; Lead; Leukocytes; Ligands; Lymphocyte; Lymphoid; Mediating; Modeling; Modification; Mouse Strains; Mus; Myelin; Organ; Pathway interactions; Phase; Phenotype; Play; Principal Investigator; Production; Property; Published Comment; Regulatory T-Lymphocyte; Relative (related person); Risk; Role; Self-control as a personality trait; Signal Transduction; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Vascular Endothelial Cell; Viral; Work; base; cell type; cytokine; immunopathology; in vivo; insight; interest; macrophage; microorganism; novel; programs; response; therapeutic target; tool; tumor

DESCRIPTION (provided by applicant): The overall goal of this project is to dissect the roles of the PD-1: PD-1 ligand pathway in regulating tolerance and autoimmunity. During the current funding period, we have found that PD-1 and it ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), have critical roles in regulating the balance between T cell activation and tolerance. Our studies indicate that PD-1, PD-L1 and PD-L2 limit the responses of both naove and effector self-reactive T cells. We have found that PD-L1 and PD-L2 can have overlapping roles on APC, but that PD-L1 on nonhematopoietic cells has a unique role in mediating tissue tolerance. The therapeutic potential of manipulating PD-1 and its ligands to ameliorate autoimmune disease gives impetus to further investigation of how these important immunoregulatory molecules modulate tolerance and autoimmunity. Our finding that PD- L1 on nonhematopoietic cells can inhibit T cell activation and effector function compels us to investigate how PD-L1 mediates tissue tolerance, and dissect the contributions of PD-L1 on T cells, APC, endothelial and other cell types in regulating T cell responses. Our results lead us to hypothesize that PD-1 and its ligands critically regulate the balance between pathogenic vs. protective T cell responses at multiple levels, both in the lymphoid organs and in the target tissues. To investigate this hypothesis, our specific aims are: 1) To compare the roles of PD-1 and its ligands in controlling the development and function of pathogenic myelin-reactive CD4 T cells. We will study the roles of PD-1 and its ligands in regulating the differentiation of myelin-reactive CD4 T cells to Th1, Th17 vs. FoxP3+ CD4 regulatory T cells, the effector functions of MOG-reactive Th1 vs. Th17 cells and the interplay between pathogenic Th1/Th17 effector cells and FoxP3+ regulatory T cells during the development and progression of EAE. 2) To investigate the role of the PD-1:PD-L pathway in regulating autopathogenic B cells. PD-1 and PD-L1 are expressed on B cells as well as T cells, but their roles in controlling self-reactive T vs. B cell responses are not clear. Dysregulated B cell responses may play a role in the exacerbated EAE that develops in PD-1-/- and PD-L-/- mice. We will investigate the roles of PD-1 and its ligands in the APC function of B cells, T cell: B cell collaboration and production of pathogenic antibodies by myelin-specific B cells. 3) To investigate the roles of PD-L1 and PD-L2 in tissue tolerance. We will study the roles of PD-L1 and PD-L2 in tolerance-inducing functions of dendritic cells and the role of PD-L1 on vascular endothelial cells in mediating tissue tolerance during EAE. We will use MOG 35-55/IAb tetramer together with MOG TCR transgenic, B cell IgH knockin mice and our PD-1-/-, PD-L1-/-, PD-L2-/- PD-L1/L2-/- mice to investigate how PD-1, PD-L1 and PD-L2 control tolerance and autoimmunity. These studies should further our understanding of mechanisms that control tolerance and autoimmunity, and provide insight into how PD-1 and its ligands may be effectively manipulated for therapy of autoimmune diseases.Project Narrative One of the most remarkable properties of the normal immune system is its ability to respond to and protect against a diversity of microorganisms, but not respond harmfully to cells or tissues of the human body. When regulatory mechanisms go awry, the immune system can attack the body and cause autoimmune disease. This project studies the mechanisms by which one important immunoregulatory pathway, the PD-1:PD-1 ligand pathway, regulates the responses of white blood cells, called lymphocytes, and protects against autoimmunity.

描述（由申请方提供）：本项目的总体目标是剖析PD-1：PD-1配体途径在调节耐受性和自身免疫性中的作用。在目前的资助期间，我们发现PD-1及其配体PD-L1（B7-H1）和PD-L2（B7-DC）在调节T细胞活化和耐受性之间的平衡方面具有关键作用。我们的研究表明，PD-1，PD-L1和PD-L2限制了原始和效应自身反应性T细胞的反应。我们发现PD-L1和PD-L2对APC可能具有重叠的作用，但非造血细胞上的PD-L1在介导组织耐受性方面具有独特的作用。操纵PD-1及其配体以改善自身免疫性疾病的治疗潜力推动了进一步研究这些重要的免疫调节分子如何调节耐受性和自身免疫性。我们发现非造血细胞上的PD-L1可以抑制T细胞活化和效应子功能，这迫使我们研究PD-L1如何介导组织耐受，并剖析T细胞、APC、内皮细胞和其他细胞类型上的PD-L1在调节T细胞应答中的作用。我们的研究结果使我们假设PD-1及其配体在淋巴器官和靶组织中在多个水平上严格调节致病性与保护性T细胞应答之间的平衡。为了研究这一假设，我们的具体目标是：1）比较PD-1及其配体在控制致病性髓鞘反应性CD 4 T细胞的发育和功能中的作用。我们将研究PD-1及其配体在调节髓磷脂反应性CD 4 T细胞向Th 1、Th 17与FoxP 3 + CD 4调节性T细胞分化中的作用，MOG反应性Th 1与Th 17细胞的效应功能以及致病性Th 1/Th 17效应细胞与FoxP 3+调节性T细胞在EAE发生和发展过程中的相互作用。2)研究PD-1：PD-L通路在调节自身致病性B细胞中的作用。PD-1和PD-L1在B细胞以及T细胞上表达，但它们在控制自身反应性T细胞对B细胞应答中的作用尚不清楚。失调的B细胞应答可能在PD-1-/-和PD-L-/-小鼠中发生的加重的EAE中发挥作用。我们将研究PD-1及其配体在B细胞的APC功能、T细胞：B细胞协作以及髓鞘特异性B细胞产生致病性抗体中的作用。3)研究PD-L1和PD-L2在组织耐受中的作用。我们将研究PD-L1和PD-L2在树突状细胞诱导耐受功能中的作用，以及PD-L1在血管内皮细胞介导EAE组织耐受中的作用。我们将使用MOG 35-55/IA B四聚体与MOG TCR转基因、B细胞IgH敲入小鼠和我们的PD-1-/-、PD-L1-/-、PD-L2-/- PD-L1/L2-/-小鼠一起研究PD-1、PD-L1和PD-L2如何控制耐受性和自身免疫。这些研究将进一步加深我们对控制耐受性和自身免疫性的机制的理解，并为如何有效地操纵PD-1及其配体用于治疗自身免疫性疾病提供见解。 正常免疫系统最显著的特性之一是它能够对多种微生物做出反应并进行保护，但不会对人体的细胞或组织做出有害的反应。当调节机制出错时，免疫系统可以攻击身体并引起自身免疫性疾病。该项目研究一种重要的免疫调节途径PD-1：PD-1配体途径调节白色血细胞（称为淋巴细胞）的反应并防止自身免疫的机制。