Immunomodulatory implications of lymphangiogenesis in allergic airway inflammation
Immunomodulatory implications of lymphangiogenesis in allergic airway inflammation
批准号:
9192731
负责人:
Katharina Maisel
金额:
$5.43万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-01 至 2018-08-31
关键词:
AcuteAddressAffectAllergensAllergicAnti-Inflammatory AgentsAnti-inflammatoryAntigen PresentationAntigen-Presenting CellsAntigensAsthmaBiological ModelsCD4 Positive T LymphocytesCD8B1 geneCell CommunicationCellsChronicComplexDataDendritic CellsDevelopmentDiseaseDonkeysDoseEducationEnzyme-Linked Immunosorbent AssayExtrinsic asthmaFlow CytometryFutureGrowthHelper-Inducer T-LymphocyteHistocompatibility Antigens Class IHistologyImmuneImmune responseImmune systemImmunityImmunologicsImmunologyInflammationInflammatoryInflammatory ResponseKnowledgeLabelLiquid substanceLungLymphangiogenesisLymphaticLymphatic Endothelial CellsLymphocyteMHC Class II GenesMemoryModelingMusNeoplasm MetastasisOutcomePeripheralPhenotypePlayPopulationProtein AnalysisPumpPyroglyphidaeRecruitment ActivityRegulatory T-LymphocyteResearchResolutionRestRoleShapesT cell differentiationT-Cell ActivationT-LymphocyteTestingTh2 CellsTissuesTumor AntigensVascular Endothelial Growth Factor CVascular Endothelial Growth Factor Receptor-3Wild Type MouseWorkadaptive immunityairway inflammationallergic airway inflammationallograft rejectionbasecytokineexhaustionimmunopathologyinsightinterstitial cellkidney allograftlymph nodeslymphatic vesselmemory CD4 T lymphocytemouse modelnew therapeutic targetnovelnovel therapeuticsprogrammed cell death ligand 1receptorresponsetumoruptake
中文摘要
项目摘要
这些细胞主要被认为是它们的液体运输作用,从间质中排出液体和细胞。
间隙和外周组织。事实上,多年的研究已经揭示了淋巴管系统
泵出液体并将免疫细胞运送到引流淋巴结。在慢性炎症条件下,如
如气道炎症、淋巴管生长和扩张增加或淋巴管生成(LAG),
已经被认为适应淋巴细胞运输增加的需要1 -8。然而,最近我们的实验室
和其他人发现,免疫细胞不仅仅是穿梭免疫细胞:它们在免疫细胞中起着关键作用。
调节免疫反应。事实上,淋巴管内皮细胞(LEC)可以摄取并呈递抗原,
适应性免疫系统和表达共刺激分子,其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LAG与对肿瘤抗原的耐受性增加有关,
以及转移和急性肾移植排斥反应,表明LAG也具有免疫调节作用。
fects3,4,14-17.然而,这些影响是什么,以及这些药物和LAG是否会导致疾病,
对持久性或分辨率知之甚少。本项目旨在了解这些免疫学的影响
在慢性过敏性气道炎症的模型系统中。我们有初步的数据表明,
阻断LAG并特异性地删除允许LEC-免疫细胞相互作用的分子,
免疫反应。因此,我的假设是,LEC,特别是在扩展状态下,发挥调节作用,
在慢性变应性气道炎症中帮助形成适应性炎症反应的作用。为了验证这一
假设我将使用流式细胞术、组织学、qPCR和通过ELISA蛋白质分析来确定如何阻断-
使用LAG改变慢性过敏性气道炎症的免疫反应,特别是观察其影响
调节免疫细胞和记忆反应(目标1)。另外,我会用荧光标记的抗-
评估肺淋巴管及其引流淋巴中过敏原的分布和吸收
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性免疫
响应(目标2)。拟议项目的结果将介绍LEC和LAG在调节
慢性变应性气道炎症的免疫反应此外,这将提供重要的知识,
可以为慢性过敏性气道炎症的新疗法的开发提供信息。
英文摘要
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.
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会议论文
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依托单位:
海外基金