Immunomodulatory implications of lymphangiogenesis in allergic airway inflammation

项目摘要 淋巴管的主要作用是转运液体和间质中的细胞。 空间和周围组织。事实上，多年的研究已经揭示了淋巴管系统是如何 泵出液体并将免疫细胞运送到引流的淋巴结节。在慢性炎症条件下，如 如呼吸道炎症，淋巴管生长和扩张增加，或淋巴管生成(LAG)， 一直被认为可以满足日益增长的淋巴细胞交易需求1-8。不过，最近我们实验室 其他人发现，淋巴管不仅仅是穿梭免疫细胞：它们在 调节免疫反应。事实上，淋巴内皮细胞(LECs)可以摄取和呈递抗原 适应性免疫系统和表达的共刺激分子可以功能失调地激活适应性免疫系统 免疫细胞9-13。此外，肿瘤中的滞后与对肿瘤抗原的耐受性增加有关，如 以及转移和急性肾移植排斥反应，表明LAG也有免疫调节作用。 3，4，14-17。然而，这些影响是什么，淋巴管和LAG是否导致疾病。 人们对一致性或解决方案知之甚少。这个项目试图了解这些免疫学意义。 在慢性过敏性呼吸道炎症的模型系统中。我们有初步数据表明， 阻断LAG并特别是删除允许LEC与免疫细胞相互作用的分子会加剧ADAP- 主动免疫反应。因此，我的假设是，LEC，特别是在扩张状态下，发挥调节作用-- RY在慢性过敏性呼吸道炎症中帮助形成适应性炎症反应的作用。为了测试这一点 假设I将使用流式细胞术、组织学、定量聚合酶链式反应和通过酶联免疫吸附试验的蛋白质分析来确定阻断- ING LAG改变慢性过敏性呼吸道炎症的免疫反应，特别是观察其影响 关于调节性免疫细胞和记忆反应(目标1)。此外，我将使用荧光标记的反- 评估变应原在肺淋巴管及其引流淋巴中的分布和摄取 节点，以及一种新的小鼠模型，以评估LEC-免疫细胞相互作用如何改变过敏免疫 回应(目标2)。拟议项目的结果将介绍LECs和LAG在调节中的作用 慢性过敏性呼吸道炎症的免疫反应。此外，这将提供至关重要的知识， 可以为慢性过敏性呼吸道炎症的新疗法的开发提供信息。

Project Summary The lymphatics are mainly recognized for their fluid transport roles, draining liquid and cells from interstitial spaces and peripheral tissues. Indeed, many years of research have revealed ow the lymphatic vasculature pumps fluid and shuttles immune cells to the draining lymph nodes. In chronic inflammatory conditions, such as airway inflammation, increased growth and expansion of lymphatic vessels, or lymphangiogenesis (LAG), has been thought to accommodate for the increased need lymphocyte trafficking1-8. However, recently our lab and others have found that the lymphatics do more than just shuttle immune cells: they play critical roles in modulating immune responses. Indeed, lymphatic endothelial cells (LECs) can take up and present antigen to the adaptive immune system and express costimulatory molecules that can dysfunctionally activate adaptive immune cells9-13. In addition, LAG in tumors has been associated with increased tolerance to tumor antigens as well as metastasis, and acute renal allograft rejection, indicating that LAG also has immunomodulatory ef- fects3,4,14-17. However, what these effects are and whether the lymphatics and LAG contribute to disease per- sistence or resolution is poorly understood. This project seeks to understand these immunological implications in a model system of chronic allergic airway inflammation. We have preliminary data that indicates that the blocking LAG and specifically deleting molecules that allow LEC-immune cell interactions exacerbate the adap- tive immune response. Therefore, my hypothesis is that LECs, particularly in an expanded state, play regulato- ry roles that help shape the adaptive inflammatory response in chronic allergic airway inflammation. To test this hypothesis I will use flow cytometry, histology, qPCR, and protein analysis via ELISA to determine how block- ing LAG alters the immune response in chronic allergic airway inflammation, specifically looking at the effects on regulatory immune cells and the memory response (Aim 1). In addition, I will use fluorescently labeled anti- gens to assess the distribution and uptake of allergens in the lymphatics of the lung and its draining lymph nodes, as well as a novel mouse-model to assess how LEC-immune cell interactions alter the allergic immune response (Aim 2). The results of the proposed project will introduce the role of LECs and LAG in modulating the immune response in chronic allergic airway inflammation. Additionally, this will provide vital knowledge that can inform the development of novel therapies for chronic allergic airway inflammation.