Inflammatory Control of Lymphocyte Trafficking

淋巴细胞运输的炎症控制

• 批准号: 8204839
• 负责人: Sharon S Evans
• 金额: $ 47.37万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204839
• 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; 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 microscopy; lymph nodes; mast cell; migration; monocyte; new therapeutic target; novel; pathogen; public health relevance; response; thermal stress; trafficking

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. PUBLIC HEALTH RELEVANCE: This proposal addresses fundamental questions in immunology regarding the mechanisms governing trafficking of lymphocytes to lymphoid organs during acute inflammation, a function that is crucial for host protection against pathogens. The molecular mechanisms that mediate basal trafficking of lymphocytes to lymphoid organs are well defined, however, little is known about the means of augmenting lymphocyte trafficking during acute inflammation. The proposed studies are expected to provide important insights into the unique role of cytokines in dynamically regulating leukocyte trafficking at key vascular checkpoints. These studies further have the potential to lead to novel therapeutic targets for the promotion of immune surveillance as well as for the treatment of chronic inflammation.

描述(申请人提供)：急性炎症反应的一个重要组成部分是快速动员血液中的淋巴细胞进入次级淋巴器官。在保护性免疫的启动过程中，这些器官是淋巴细胞与抗原和外来病原体相遇的集结地。在定义黏附事件方面已经取得了重大进展，这些黏附事件指导淋巴细胞通过淋巴器官中的血管检查点进行稳态的稳态运输。相比之下，炎症期间幼稚和中央记忆细胞向淋巴器官可诱导运输的分子基础却知之甚少。大量的初步数据使我们假设，在急性炎症过程中，促炎症细胞因子白介素6(IL-6)是调节淋巴细胞迁移到淋巴器官的驱动力。第一个目标是在全身发热性炎症模型中确定调节血管网关捕获效率的IL-6的细胞来源。野生型和IL-6缺陷小鼠的相互骨髓嵌合体将分开，在发热应激期间，增强淋巴细胞跨血管壁运输需要耐辐射基质细胞还是辐射敏感造血细胞产生IL-6。归巢试验和活体显微镜将进一步验证确定的IL-6细胞来源促进淋巴细胞流入淋巴器官。目标2将侧重于确定在适应性免疫反应过程中，IL-6是否也负责动员幼稚细胞到局部炎症的淋巴结内募集。这些研究是基于我们令人惊讶的发现，成熟树突状细胞产生的IL-6改变了血管入口的黏附特性。最终目标将使用遗传学方法来剖析IL-6下游信号转导通路，这些信号转导通路在局部和全身适应性免疫反应期间调节淋巴细胞运输。这项研究将使用在IL-6信号通路中存在特定缺陷的突变小鼠品系，以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所需的细胞因子可能会导致慢性炎症性疾病的新干预策略，并为基于IL-6提高适应性免疫能力的疫苗方法提供见解。 公共卫生相关性：这项建议解决了免疫学中的基本问题，即在急性炎症期间控制淋巴细胞向淋巴器官运输的机制，这一功能对于宿主保护免受病原体的伤害至关重要。介导淋巴细胞基础转运到淋巴器官的分子机制已被很好地阐明，然而，关于在急性炎症期间增加淋巴细胞转运的方法知之甚少。这项拟议的研究有望为细胞因子在动态调节关键血管检查点的白细胞运输中的独特作用提供重要的见解。这些研究进一步有可能导致新的治疗目标，以促进免疫监测以及治疗慢性炎症。