Immunomodulatory roles of lymphatic vessels in allergic airway inflammation

淋巴管在过敏性气道炎症中的免疫调节作用

基本信息

  • 批准号:
    9300618
  • 负责人:
  • 金额:
    $ 24.21万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-02-01 至 2019-01-31
  • 项目状态:
    已结题

项目摘要

Project Summary Lymphatic vessels serve as transporters for immune cells, shuttling them together with antigens, cytokines and other factors from peripheral tissues to the draining lymph nodes, where immune responses are shaped. Aside from this transport function, there is emerging evidence, from our lab and others, suggesting that lymphatic vessels may play many other roles in regulating immunity; for example, lymphatic endothelial cells (LECs) can secrete immunosuppressive cytokines and present antigen on MHC class I and II molecules for T cell activa- tion. Lymphatic vessel expansion, or lymphangiogenesis, occurs in allergic airway inflammation associated with asthma, along with many other chronic inflammatory diseases; however, it is unknown how lymphangio- genesis impacts the immunopathology. Using a house dust mite (HDM) mouse model of allergic airway in- flammation, we found that lymphangiogenesis was occurring, indicating that the lymphatic growth factor VEGF- C was upregulated. VEGF-C induced LECs to not only proliferate but also activate CCL21, which recruits na- ïve, regulatory and memory T cell subsets. When we subsequently blocked VEGF-C signaling (with a blocking antibody against its receptor, VEGFR-3) during HDM challenge, we found that these T cell subsets in the lung were reduced, indicating that VEGF-C-activated LECs enhance T cell recruitment and trafficking during allergic airway inflammation and may thereby exacerbate the pathology. On the other hand, our lab recently demon- strated that LECs are able to directly interact with naïve CD4+ T cells, which mediate allergic inflammatory re- sponses, to potentially induce anergy or suppression. In vitro, we found that LECs upregulate MHCII molecules upon inflammatory stimuli and that LEC-T cell interactions can lead to T cell proliferation. To explore the role of direct LEC-CD4+ T cell interactions in vivo, we developed a mouse model with an inducible, LEC-specific MHCII deletion. In preliminary experiments challenging these mice with HDM, we found that the Th2 response was exacerbated at early times, potentially suggesting that MHCII expression by LECs may play immunoregu- latory (i.e., protective) roles in allergic airway inflammation. Taken together, these preliminary findings led us to hypothesize that lymphangiogenesis plays both protective and pathological roles in allergic airway inflamma- tion. To test this, we will 1) Determine the role of VEGF-C signaling during allergic airway inflammation, 2) De- termine the extent to which LECs can directly and indirectly suppress T cell activation and alter differentiation, and 3) Determine if lymphangiogenesis is detrimental in long-term allergic airway inflammation.
项目摘要 淋巴管充当免疫细胞的运输者,将它们与抗原、细胞因子和 从外周组织到引流淋巴结的其他因素,在那里形成免疫反应。搁置一边 从这种转运功能来看,来自我们实验室和其他实验室的新证据表明,淋巴 血管可能在调节免疫方面发挥许多其他作用;例如,淋巴管内皮细胞(LECs)可以 分泌免疫抑制细胞因子,并在MHC I和II类分子上提呈抗原,以激活T细胞 提顿。淋巴管扩张,或淋巴管生成,发生在与过敏性呼吸道炎症相关的 哮喘以及许多其他慢性炎症性疾病;然而,淋巴血管如何- 《创世纪》对免疫病理学的影响。使用室内尘螨(HDM)小鼠模型的过敏性呼吸道- 炎症时,我们发现淋巴管生成正在发生,表明淋巴管生长因子血管内皮生长因子-1 C表达上调。血管内皮生长因子-C不仅能诱导晶状体上皮细胞增殖,而且还能激活CCL21,从而招募NA-C。 幼稚、调节性和记忆性T细胞亚群。当我们随后阻断血管内皮生长因子-C信号时(通过阻断 抗其受体VEGFR-3的抗体)在HDM攻击期间,我们发现肺中的这些T细胞亚群 减少,表明血管内皮生长因子C激活的LECs在过敏过程中促进T细胞的募集和运输 呼吸道炎症,从而可能加重病理。另一方面,我们的实验室最近发现了- 研究表明,LEC能够直接与幼稚的CD4+T细胞相互作用,介导变态反应性炎症反应。 应答,潜在地引起无能或抑制。在体外,我们发现晶状体上皮细胞上调MHCII分子 在炎症刺激下,LEC-T细胞的相互作用可导致T细胞的增殖。探索……的作用 体内LEC-CD4+T细胞的直接相互作用,我们建立了一种可诱导的、LEC特异性的小鼠模型 MHCII删除。在用HDM挑战这些小鼠的初步实验中,我们发现Th2反应 早期加重,可能提示LECs表达MHCII可能发挥免疫调节作用。 在过敏性呼吸道炎症中起到保护作用。综上所述,这些初步发现让我们得出了 假设淋巴管生成在过敏性气道炎中起到保护和病理作用。 提顿。为了测试这一点,我们将1)确定血管内皮生长因子-C信号在过敏性气道炎症中的作用,2)去... 终止LEC直接和间接抑制T细胞激活和改变分化的程度, 以及3)确定淋巴管生成在长期过敏性呼吸道炎症中是否有害。

项目成果

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Melody Ann Swartz其他文献

Melody Ann Swartz的其他文献

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{{ truncateString('Melody Ann Swartz', 18)}}的其他基金

Probing cellular, molecular and biomechanical barriers to immunotherapy in the tumor microenvironment with organotypic in vitro models of the tumor-lympho-immune interface
利用肿瘤-淋巴-免疫界面的器官型体外模型探索肿瘤微环境中免疫治疗的细胞、分子和生物力学障碍
  • 批准号:
    10457432
  • 财政年份:
    2021
  • 资助金额:
    $ 24.21万
  • 项目类别:
Probing cellular, molecular and biomechanical barriers to immunotherapy in the tumor microenvironment with organotypic in vitro models of the tumor-lympho-immune interface
利用肿瘤-淋巴-免疫界面的器官型体外模型探索肿瘤微环境中免疫治疗的细胞、分子和生物力学障碍
  • 批准号:
    10696126
  • 财政年份:
    2021
  • 资助金额:
    $ 24.21万
  • 项目类别:
Probing cellular, molecular and biomechanical barriers to immunotherapy in the tumor microenvironment with organotypic in vitro models of the tumor-lympho-immune interface
利用肿瘤-淋巴-免疫界面的器官型体外模型探索肿瘤微环境中免疫治疗的细胞、分子和生物力学障碍
  • 批准号:
    10299447
  • 财政年份:
    2021
  • 资助金额:
    $ 24.21万
  • 项目类别:
Probing cellular, molecular and biomechanical barriers to immunotherapy in the tumor microenvironment with organotypic in vitro models of the tumor-lympho-immune interface
利用肿瘤-淋巴-免疫界面的器官型体外模型探索肿瘤微环境中免疫治疗的细胞、分子和生物力学障碍
  • 批准号:
    10533678
  • 财政年份:
    2021
  • 资助金额:
    $ 24.21万
  • 项目类别:
Probing cellular, molecular and biomechanical barriers to immunotherapy in the tumor microenvironment with organotypic in vitro models of the tumor-lympho-immune interface
利用肿瘤-淋巴-免疫界面的器官型体外模型探索肿瘤微环境中免疫治疗的细胞、分子和生物力学障碍
  • 批准号:
    10681942
  • 财政年份:
    2021
  • 资助金额:
    $ 24.21万
  • 项目类别:
Probing cellular, molecular and biomechanical barriers to immunotherapy in the tumor microenvironment with organotypic in vitro models of the tumor-lympho-immune interface
利用肿瘤-淋巴-免疫界面的器官型体外模型探索肿瘤微环境中免疫治疗的细胞、分子和生物力学障碍
  • 批准号:
    10737791
  • 财政年份:
    2021
  • 资助金额:
    $ 24.21万
  • 项目类别:
Paradoxical roles of tumor lymphangiogenesis on tumor immunity and implications for immunotherapy - Resubmission 01
肿瘤淋巴管生成对肿瘤免疫的矛盾作用及其对免疫治疗的影响 - 重新提交 01
  • 批准号:
    10368055
  • 财政年份:
    2018
  • 资助金额:
    $ 24.21万
  • 项目类别:
Paradoxical roles of tumor lymphangiogenesis on tumor immunity and implications for immunotherapy - Resubmission 01
肿瘤淋巴管生成对肿瘤免疫的矛盾作用及其对免疫治疗的影响 - 重新提交 01
  • 批准号:
    9891035
  • 财政年份:
    2018
  • 资助金额:
    $ 24.21万
  • 项目类别:
2014 Molecular Mechanisms in Lymphatic Function and Disease Gordon Research Confe
2014年淋巴功能与疾病的分子机制戈登研究会议
  • 批准号:
    8718874
  • 财政年份:
    2014
  • 资助金额:
    $ 24.21万
  • 项目类别:
Lymph vs. blood angiogenesis: functional differences
淋巴与血管生成:功能差异
  • 批准号:
    6710442
  • 财政年份:
    2003
  • 资助金额:
    $ 24.21万
  • 项目类别:

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