Inflammatory Control of Lymphocyte Trafficking

淋巴细胞运输的炎症控制

基本信息

批准号：
8602800
负责人：
Sharon S Evans
金额：
$ 48.74万
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：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8602800
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 Immune Immune response Immune system Immunity Immunologic Surveillance Immunology In Situ Inflammation Inflammatory Inflammatory Response Intercellular adhesion molecule 1 Interleukin-6 Intervention Knockout Mice Laboratories Lead Leukocyte Trafficking Link Lymphatic Lymphocyte Lymphoid MEKs Malignant Neoplasms Maps Mediating Memory Modeling Molecular Mus Mutant Strains Mice Organ PNAd PTPN11 gene Pathway interactions Phase Physiologic pulse Play Probability Process Production Property Radiation Ras/Raf Resistance Reticular Cell Role STAT3 gene Signal Pathway Signal Transduction Pathway Site Source Staging Stress Stromal Cells T memory cell T-Lymphocyte Transgenic Organisms Vaccines adaptive immunity base chemokine cytokine density driving force immunopathology insight intravital imaging intravital microscopy lymph nodes mast cell migration monocyte new therapeutic target novel pathogen public health relevance response thermal stress trafficking

项目摘要

DESCRIPTION (provided by applicant): 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 naive 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 naive cells to local inflamed lymph nodes during an adaptive immune response. These studies are based on our surprising discovery that IL-6 produced by mature dendritic cells 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. The studies will use mutant mouse lines that have specific defects in IL-6 signaling pathways in order to map the molecular mechanisms 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 IL-6 to heighten adaptive immunity.

描述（由申请人提供）：急性炎症反应的一个关键组成部分是血源性淋巴细胞快速动员至次级淋巴器官。这些器官是淋巴细胞在保护性免疫启动过程中遇到抗原和外来病原体的舞台。在定义粘附事件方面已经取得了重大进展，这些粘附事件指导淋巴细胞穿过淋巴器官血管检查点的稳态运输。相比之下，炎症期间幼稚记忆细胞和中央记忆细胞向淋巴器官的诱导运输的分子基础尚不清楚。大量的初步数据使我们推测促炎细胞因子白细胞介素 6 (IL-6) 是急性炎症期间调节淋巴细胞迁移到淋巴器官的驱动力。第一个目标是确定 IL-6 的细胞来源，该细胞来源可调节全身性发热炎症模型中血管通道的捕获效率。野生型和 IL-6 缺陷型小鼠的相互骨髓嵌合体将区分热应激期间增强淋巴细胞跨血管壁运输是否需要抗辐射基质细胞或辐射敏感造血细胞产生 IL-6。归巢测定和活体显微镜检查将进一步验证特定细胞来源的 IL-6 促进淋巴细胞流入淋巴器官。目标 2 将重点确定 IL-6 是否也负责在适应性免疫反应过程中动员幼稚细胞至局部发炎的淋巴结。这些研究基于我们令人惊讶的发现，即成熟树突状细胞产生的 IL-6 可以改变血管入口的粘附特性。最终目标将使用遗传学方法剖析在局部和全身适应性免疫反应期间调节淋巴细胞运输的 IL-6 下游信号转导途径。这些研究将使用在 IL-6 信号通路中具有特定缺陷的突变小鼠系来绘制急性炎症期间加速淋巴细胞运输所需的分子机制。了解急性炎症期间淋巴细胞募集的细胞因子需求可能会导致慢性炎症性疾病的新干预策略，并为基于 IL-6 增强适应性免疫能力的疫苗方法提供见解。