Inflammatory Control of Lymphocyte Trafficking

淋巴细胞运输的炎症控制

基本信息

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
项目类别：
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

项目摘要

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，这些器官是集结地。淋巴细胞在启动过程中遇到抗原和外来病原体在定义粘附事件方面取得了重大进展。指导淋巴细胞穿过血管检查点的稳态运输相比之下，诱导性运输的分子基础。 ve 和中央炎症期间记忆细胞对淋巴器官的影响尚不清楚。初步数据使我们认为促炎细胞因子白细胞介素 6 (IL-6) 是急性期调节淋巴细胞迁移至淋巴器官的驱动力第一个目标是确定调节捕获的 IL-6 的细胞来源。全身性发热炎症模型中血管通路的效率。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发热应激期间增强淋巴细胞跨血管壁运输所需的。归巢测定和活体显微镜检查将进一步验证确定的细胞来源 IL-6 促进淋巴细胞流入淋巴器官目标 2 将重点确定 IL-6 是否存在。还负责动员招募新兵ve 细胞到达局部发炎的淋巴结这些研究基于我们发现 IL-6。由成熟的树突产生的改变了血管入口的粘附特性。最终目标是利用遗传学方法剖析 IL-6 下游信号转导局部和全身适应性免疫系统中调节淋巴细胞运输的途径这些研究将使用具有特定 IL-6 缺陷的突变小鼠系。信号通路，以绘制加速所需的分子机制了解急性炎症期间淋巴细胞的运输。急性炎症期间的福细胞淋巴募集可能会导致新的干预措施慢性炎症性疾病的策略以及提供对疫苗的见解基于细胞因子增强适应性免疫能力的方法。