Inflammatory Control of Lymphocyte Trafficking

淋巴细胞运输的炎症控制

• 批准号: 7847761
• 负责人: Sharon S Evans
• 金额: $ 25.61万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847761
• 关键词: Acute; Address; Adhesions; Adhesives; Antigens; Autoimmune Diseases; Automobile Driving; Biological Assay; Blood; Blood Vessels; Bone Marrow; CCL21 gene; Cells; Chimera organism; Chronic; Cues; Cytokine Signaling; Data; Defect; Dendritic Cells; Disease; Endothelial Cells; Event; Fever; Genetic; Hematopoietic; High Endothelial Venule; Homing; Image; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunology; In Situ; Inflammation; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Interleukin-6; Intervention; Laboratories; Lead; Leukocyte Trafficking; Link; Lymphatic; Lymphocyte; Lymphoid; Malignant Neoplasms; Maps; Mediating; Memory; Modeling; Molecular; Mus; Mutant Strains Mice; Organ; PNAd; Pathway interactions; Phase; Physiologic pulse; Play; Probability; Process; Production; Property; Radiation; Regulation; Resistance; Reticular Cell; Role; Signal Pathway; Signal Transduction Pathway; Site; Source; Staging; Stress; Stromal Cells; T memory cell; T-Lymphocyte; Transgenic Organisms; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Vaccines; base; chemokine; cytokine; density; driving force; immunopathology; in vivo Model; insight; intravital microscopy; lymph nodes; mast cell; migration; monocyte; new therapeutic target; novel; pathogen; response; thermal stress; trafficking

A critical component of the acute inflammatory response is the rapid mobilization of blood- borne lymphocytes into secondary lymphoid organs. These organs are the staging ground for lymphocyte encounters with antigens and foreign pathogens during the initiation of protective immunity. Significant progress has been achieved in defining the adhesion events that guide homeostatic steady-state trafficking of lymphocytes across vascular checkpoints in lymphoid organs. By contrast, the molecular basis of inducible trafficking of na¿ve and central memory cells to lymphoid organs during inflammation is poorly understood. Extensive preliminary data lead us to hypothesize that the proinflammatory cytokine, interleukin-6 (IL-6), is a driving force in regulating lymphocyte migration into lymphoid organs during acute inflammation. The first aim will identify the cellular source of IL-6 that regulates the capture efficiency of vascular gateways in a model of systemic febrile inflammation. Reciprocal bone marrow chimeras with wild-type and IL-6-deficient mice will segregate whether IL-6 production by radiation-resistant stromal cells or radiation-sensitive hematopoietic cells is required for enhanced lymphocyte trafficking across vessel walls during febrile stress. Homing assays and intravital microscopy will further validate that a defined cellular source of IL-6 promotes lymphocyte influx into lymphoid organs. Aim 2 will focus on determining if IL-6 is also responsible for mobilizing the recruitment of na¿ve cells to local inflamed lymph nodes during an adaptive immune response. These studies are based on our discovery that IL-6 produced by mature dendritic modifies the adhesive properties of vascular entryways. The final aim will use genetic approaches to dissect the IL-6 downstream signal transduction pathways that regulate lymphocyte trafficking during local and systemic adaptive immune responses. These studies will use mutant mouse lines that have specific defects in IL-6 signaling pathways in order to map the molecular mechanism required for accelerated lymphocyte trafficking during acute inflammation. Understanding the cytokine requirements for lymphocyte recruitment during acute inflammation may lead to novel intervention strategies in chronic inflammatory disorders as well as provide insights into vaccine approaches based on the ability of cytokines to heighten adaptive immunity.

急性炎症反应的一个关键组成部分是血液的快速动员- 携带淋巴细胞进入次级淋巴器官。这些器官是 对于淋巴细胞与抗原和外来病原体的接触， 保护性免疫在定义粘连事件方面取得了重大进展 引导淋巴细胞通过血管检查点的稳态运输， 淋巴器官相比之下，诱导运输幼稚和中枢神经系统的分子基础， 记忆细胞在炎症过程中转移到淋巴器官的机制还知之甚少。广泛 初步数据使我们假设促炎细胞因子，白细胞介素-6（IL-6）， 是急性期调节淋巴细胞向淋巴器官迁移的驱动力 炎症第一个目标是确定调节捕获的IL-6的细胞来源。 全身性发热性炎症模型中血管通道的效率。交互骨 野生型和IL-6缺陷小鼠的骨髓嵌合体将分离IL-6是否 由抗辐射基质细胞或辐射敏感造血细胞产生， 在热应激期间增强淋巴细胞穿过血管壁的运输所需的。 归巢分析和活体显微镜检查将进一步证实，一个确定的细胞来源， IL-6促进淋巴细胞流入淋巴器官。目标2将集中于确定IL-6是否 也负责动员幼稚细胞到局部发炎的淋巴结 在适应性免疫反应中。这些研究是基于我们发现IL-6 由成熟的树突产生的改变血管入口通道的粘附特性。的 最后的目的是利用遗传学方法来剖析IL-6下游信号转导 在局部和全身适应性免疫过程中调节淋巴细胞运输的途径 应答这些研究将使用IL-6有特定缺陷的突变小鼠品系 信号通路，以绘制加速细胞凋亡所需的分子机制。 淋巴细胞运输在急性炎症。了解细胞因子的需求 急性炎症期间淋巴细胞募集可能导致新的干预措施 慢性炎症性疾病的治疗策略，并为疫苗提供见解 基于细胞因子提高适应性免疫能力的方法。