Inflammatory Control of Lymphocyte Trafficking

描述（由申请方提供）：急性炎症反应的一个关键组成部分是血源性淋巴细胞迅速动员进入次级淋巴器官。这些器官是淋巴细胞在保护性免疫启动期间与抗原和外来病原体相遇的舞台。在定义引导淋巴细胞跨越淋巴器官中的血管检查点的稳态稳态运输的粘附事件方面已经取得了重大进展。相比之下，在炎症过程中幼稚和中枢记忆细胞向淋巴器官的诱导性运输的分子基础知之甚少。大量的初步数据使我们假设，促炎细胞因子，白细胞介素-6（IL-6），是一种驱动力，在调节淋巴细胞迁移到淋巴器官在急性炎症。第一个目标是确定IL-6的细胞来源，其调节全身性发热性炎症模型中血管通道的捕获效率。与野生型和IL-6缺陷小鼠的相互骨髓嵌合体将分离是否需要通过辐射抗性基质细胞或辐射敏感造血细胞产生IL-6，以增强淋巴细胞在发热应激期间穿过血管壁的运输。归巢试验和活体显微镜检查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将集中于确定IL-6是否也负责在适应性免疫应答期间动员幼稚细胞向局部发炎淋巴结的募集。这些研究是基于我们令人惊讶的发现，即成熟树突状细胞产生的IL-6改变了血管入口通道的粘附特性。最终的目标将使用遗传学方法来剖析IL-6下游信号转导通路，在局部和全身适应性免疫应答过程中调节淋巴细胞的运输。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，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，并提供基于IL-6增强适应性免疫能力的疫苗方法的见解。 公共卫生相关性：该提案解决了免疫学中关于急性炎症期间淋巴细胞向淋巴器官运输的机制的基本问题，这一功能对于宿主保护免受病原体侵害至关重要。介导淋巴细胞向淋巴器官的基础运输的分子机制是明确的，然而，关于在急性炎症期间增加淋巴细胞运输的手段知之甚少。这些研究有望为细胞因子在关键血管检查点动态调节白细胞运输中的独特作用提供重要见解。这些研究进一步有可能导致新的治疗靶点，用于促进免疫监视以及治疗慢性炎症。

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.