Cellular and Genetic Analysis of Lymphocyte Egress

淋巴细胞排出的细胞和遗传分析

• 批准号: 8662682
• 负责人: Jason G Cyster
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662682
• 关键词: Address; Antigens; Autoimmune Diseases; Award; B-Lymphocytes; Blood; Blood Circulation; Blood-Borne Pathogens; Cells; Clinical; Data; Dendritic Cells; Development; Effector Cell; Epithelium; Goals; Grant; Immune; Immune System Diseases; Immune response; Immunologic Surveillance; Immunosuppressive Agents; Infection; Inflammatory; Knowledge; Ligands; Lymph; Lymphatic; Lymphatic Endothelium; Lymphatic vessel; Lymphocyte; Lymphoid; Lymphoid Tissue; Malpighian corpuscles; Microscopy; Modeling; Molecular; Movement; Multiple Sclerosis; Oral; Organ; Pathway interactions; Peripheral; Pharmaceutical Preparations; Procedures; Role; Site; Skin; Source; Sphingosine-1-Phosphate Receptor; Spleen; Splenic Red Pulp; Structure of aggregated lymphoid follicle of small intestine; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Therapeutic Agents; Thymus Gland; Time; Tissue Model; Tissues; Travel; Work; cell motility; cell type; follow-up; genetic analysis; immune function; intravital microscopy; lymph nodes; migration; novel therapeutics; response; sphingosine 1-phosphate; therapeutic development; tool; trafficking; two-photon

DESCRIPTION (provided by applicant): The molecular mechanism of cell entry from blood into tissues has been intensely studied over more than three decades. This work has led to a well-defined multistep model of tissue entry by cells and the development of approved therapeutic agents that target entry as a treatment for immunological diseases. Cell egress from tissues into circulation is equally important for immune function yet has been a focus of study for only the last several years. The potential clinical impact of developing agents to modulate cell egress has been highlighted by the September 2010 approval of FTY720 (Fingolimod), a drug that inhibits lymphocyte egress from lymphoid organs, as the first oral treatment for multiple sclerosis. FTY720 is a ligand for four of five sphingosine-1-phosphate (S1P) receptors. T and B cell egress from lymph nodes, spleen and Peyer's patches is dependent on S1P and S1P receptor-1 (S1PR1). This proposal will identify the pathway of B cell egress from the spleen into blood. Secondly, it will characterize how S1PR1 regulates marginal zone B cell movement and antigen transport between subcompartments within the spleen. Thirdly, it will explore the role of a migration- inhibitory S1P receptor, S1PR2, in controlling egress of cells from non-lymphoid tissues into lymph. This work will elucidate key requirements for lymphocyte egress from lymphoid and non-lymphoid tissues, findings that may help in the development of new therapeutics for treatment of autoimmune diseases.

描述（由申请人提供）：三十多年来，人们对细胞从血液进入组织的分子机制进行了深入研究。这项工作形成了细胞进入组织的明确多步骤模型，并开发了已批准的治疗剂，这些治疗剂以进入为目标来治疗免疫性疾病。细胞从组织进入循环系统对于免疫功能同样重要，但一直是研究的焦点 只是最近几年。 2010 年 9 月 FTY720（芬戈莫德）获得批准，凸显了开发调节细胞流出药物的潜在临床影响，FTY720 是一种抑制淋巴细胞从淋巴器官流出的药物，作为多发性硬化症的第一个口服治疗药物。 FTY720 是五种 1-磷酸鞘氨醇 (S1P) 受体中四种的配体。 T 细胞和 B 细胞从淋巴结、脾脏和派尔氏淋巴结的排出取决于 S1P 和 S1P 受体 1 (S1PR1)。该提案将确定 B 细胞从脾脏进入血液的途径。其次，它将描述 S1PR1 如何调节边缘区 B 细胞运动和脾内亚区室之间的抗原转运。第三，它将探索迁移抑制性 S1P 受体 S1PR2 在控制细胞从非淋巴组织进入淋巴中的作用。这项工作将阐明淋巴细胞从淋巴和非淋巴组织中流出的关键要求，这些发现可能有助于开发治疗自身免疫性疾病的新疗法。