TNF family members for lymph angiogenesis and lymph node hypertrophy

TNF 家族成员促进淋巴血管生成和淋巴结肥大

• 批准号: 8232145
• 负责人: YANG-XIN FU
• 金额: $ 31.4万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232145
• 关键词: Acute; Adjuvant; B-Lymphocytes; Bone Marrow; Cell Adhesion Molecules; Cells; Clinical; Data; Dendritic Cells; Dermal; Development; Disease; Endothelial Cells; Family member; Generations; Growth; High Endothelial Venule; Hypertrophy; Immigration; Immune; Immune response; Immunization; Immunotherapy; Infection; Inflammation; Inflammation Mediators; Knockout Mice; Knowledge; Langerhans cell; Leukocytes; Light; Lymph; Lymphangiogenesis; Lymphatic vessel; Malignant Neoplasms; Mediating; Membrane; Molecular; Mus; Neoplasm Metastasis; Peripheral; Process; Production; Regulation; Reticular Cell; Role; Signal Transduction; Skin; Source; Staging; Sum; T-Lymphocyte; TNF gene; Testing; Therapeutic; Tissues; Tumor Immunity; Tumor Necrosis Factor-Beta; Up-Regulation; Vaccination; Vaccines; Vascular Endothelial Growth Factors; angiogenesis; base; cell growth; cell motility; chemokine; cytokine; herpesvirus entry mediator; high voltage electron microscopy; improved; lymph nodes; mast cell; migration; mouse model; novel strategies; receptor; response; tumor

Rapid development of lymphatic vessels (LV) and high endothelial venules (HEV) in peripheral tissues leads to hypertrophy of draining lymph nodes (LN) during inflammation/vaccination, but the molecular mechanism regulating LN hypertrophy is poorly understood. Lymphotoxin (LT), TNF, mast cells, and dendritic cells have all been implicated in the regulation of LN hypertrophy after vaccination or during inflammation. Unexpectedly but intriguingly, our preliminary studies have revealed that LIGHT (TNFRSF14), which shares the LT¿R receptor with LT, is also required for LN hypertrophy, since LIGHT KO mice fail to undergo LN hypertrophy after CFA immunization. In preliminary studies using mouse models, we have also determined that Langerhans' cells, specialized dermal DCs, and mast cells are essential for LN hypertrophy after CFA immunization. We hypothesize that LIGHT from LC coordinates with membrane LT to regulate LV/HEV activation and proliferation as well as leukocyte migration into the LN in response to immune insult, leading to LN hypertrophy. Specifically, we will explore whether LIGHT from Langerhans' cells is essential to activate mast cells via LT¿R signaling to produce inflammatory mediators for rapid development of LVs and HEVs. We will also study whether B cells are the source of membrane LT required for LN hypertrophy, and how LT coordinates with LIGHT to amplify the HEV activation and promote LV/HEV endothelial cell growth. In aim 1, we will study how LIGHT mediates LN hypertrophy on a cellular level by determining which cells are required to produce and respond to LIGHT during LN hypertrophy. We will test whether Langerhans' cells are the essential LIGHT-producing cells for LN hypertrophy. We will also identify LIGHT-responding cells, which we hypothesize to be mast cells based on our preliminary data. In aim 2, we will study how LIGHT mediates LN hypertrophy on a molecular level. We will define the molecular mechanisms by which LIGHT regulates LV/HEV endothelial cells directly and/or indirectly through mast cell activation and TNF-¿ production. We will also investigate how LIGHT and TNF-¿ coordinates for LV/HEV activation at the early stage of vaccination. In aim 3, we will test whether B cells are major source of LT for LN hypertrophy and determine whether and how LIGHT and LT cooperate during LN hypertrophy. In aim 4, we will determine the role of LIGHT-mediated LN hypertrophy in tumor immunity. We will define the role of LIGHT-mediated (lymph)angiogenesis in antitumor T cell priming and explore the therapeutic potential of using Ad-LIGHT as an adjuvant to enhance (lymph)angiogenesis and DC/T cell migration for improved tumor immunotherapy. In sum, our study will elucidate cellular and molecular mechanisms that drive LN hypertrophy in response to inflammation, as well as examining the role of LIGHT-mediated DC migration in the development of functional anti-tumor immune responses and more effective vaccines. 1

外周组织中淋巴管（LV）和高内皮微静脉（HEV）的快速发育 导致炎症/疫苗接种期间引流淋巴结（LN）肥大，但其分子 调节LN肥大的机制知之甚少。光敏素（LT）、TNF、肥大细胞和 树突状细胞都参与了免疫后或免疫过程中LN肥大的调节。 炎症出乎意料但有趣的是，我们的初步研究表明， 与LT共享LT受体的TNFRSF 14也是LN肥大所必需的，因为LIGHT KO小鼠在CFA免疫后不能经历LN肥大。在使用小鼠的初步研究中 模型中，我们还确定了朗格汉斯细胞，特化的真皮DC和肥大细胞， 对于CFA免疫后LN肥大至关重要。我们假设LC的光 与膜LT协调调节LV/HEV活化和增殖， 白细胞响应免疫损伤而迁移到LN中，导致LN肥大。 具体来说，我们将探索来自朗格汉斯细胞的LIGHT是否是通过以下途径激活肥大细胞所必需的： LT R信号传导产生炎症介质，用于LV和HEV的快速发展。我们还将 研究B细胞是否是LN肥大所需的膜LT的来源，以及LT是如何产生的。 与LIGHT协调以放大HEV活化并促进LV/HEV内皮细胞生长。在aim中 1，我们将通过确定哪些细胞来研究LIGHT如何在细胞水平上介导LN肥大 LN肥大期间需要产生LIGHT并对LIGHT做出反应。我们将测试朗格汉斯细胞 是LN肥大所必需的LIGHT产生细胞。我们还将识别光反应细胞， 根据我们的初步数据我们假设是肥大细胞。在目标2中，我们将研究光如何 在分子水平上介导LN肥大。我们将定义分子机制， LIGHT通过肥大细胞活化和TNF-α直接和/或间接调节LV/HEV内皮细胞 生产我们还将研究LIGHT和TNF-α如何在早期协调LV/HEV激活， 疫苗接种阶段。在目标3中，我们将测试B细胞是否是LN肥大的LT的主要来源， 确定LIGHT和LT在LN肥大过程中是否以及如何合作。在目标4中，我们将确定 LIGHT介导的LN肥大在肿瘤免疫中的作用。我们将定义 LIGHT介导的（淋巴）血管生成在抗肿瘤T细胞引发中的作用，并探索LIGHT的治疗潜力。 使用Ad-LIGHT作为佐剂以增强（淋巴）血管生成和DC/T细胞迁移， 肿瘤免疫治疗总之，我们的研究将阐明驱动LN的细胞和分子机制 肥大反应炎症，以及检查的作用，轻介导的DC迁移 在开发功能性抗肿瘤免疫反应和更有效的疫苗方面。 1