Cellular and Genetic Analysis of Lymphocyte Egress

描述（由申请人提供）：细胞从血液进入组织的分子机制已经被深入研究了三十多年。这项工作导致了一个明确的多步骤模型的组织进入细胞和批准的治疗剂的发展，目标进入作为一种治疗免疫性疾病。细胞从组织进入循环对于免疫功能同样重要，但一直是免疫学研究的焦点。 只是最近几年。2010年9月批准FTY 720（Fingolimod）（一种抑制淋巴细胞从淋巴器官中排出的药物）作为多发性硬化症的第一种口服治疗药物，突出了开发调节细胞排出的药物的潜在临床影响。FTY 720是五种鞘氨醇-1-磷酸（S1 P）受体中四种的配体。T和B细胞从淋巴结、脾和派伊尔集合淋巴结的排出依赖于S1 P和S1 P受体1（S1 PR 1）。该建议将确定B细胞从脾脏进入血液的途径。其次，它将表征S1 PR 1如何调节边缘区B细胞运动和脾内亚室之间的抗原转运。第三，它将探索迁移抑制S1 P受体S1 PR 2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。 公共卫生相关性：淋巴细胞从淋巴器官流出对于免疫监视和新激活的效应细胞到达感染部位是必要的。这项工作将确定淋巴细胞从脾脏进入血液的途径。其次，它将表征抗原转运B细胞在脾内隔室之间移动的要求。最后，它将定义一种调节细胞从皮肤进入淋巴管的机制。这项工作有可能为免疫抑制药物和自身免疫性疾病的治疗确定新的靶点。

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. PUBLIC HEALTH RELEVANCE: Lymphocyte egress from lymphoid organs is necessary for immune surveillance and for newly activated effector cells to reach sites of infection. This work will identify the pathway of lymphocyte egress from the spleen into blood. Secondly, it will characterize requirements for antigen-transporting B cell movement between compartments within the spleen. Finally, it will define a mechanism regulating cell movement from the skin into lymphatic vessels. The work has the potential of identifying new targets for immunosuppressive drugs and treatment of autoimmune diseases.