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

基本信息

批准号：
8448978
负责人：
YANG-XIN FU
金额：
$ 29.52万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
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/8448978
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

项目摘要

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）的快速发育在炎症/疫苗接种期间导致引流淋巴结（LN）肥大，但分子淋巴毒素 (LT)、肿瘤坏死因子、肥大细胞和淋巴毒素的调节机制尚不清楚。树突状细胞都与疫苗接种后或接种过程中 LN 肥大的调节有关。出乎意料但有趣的是，我们的初步研究表明，光。（TNFRSF14），共享 LT¿ R 受体与 LT 也是 LN 肥大所必需的，因为 LIGHT 在使用小鼠进行的初步研究中，KO 小鼠在 CFA 免疫后未能出现 LN 肥大。模型中，我们还确定了朗格汉斯细胞、特化真皮 DC 和肥大细胞 CFA 免疫后 LN 肥大至关重要，我们从 LC 中获得了光。与膜 LT 协调调节 LV/HEV 激活和增殖以及白细胞因免疫损伤而迁移至淋巴结，导致淋巴结肥大。具体来说，我们将探讨朗格汉斯细胞发出的光是否对于通过以下方式激活肥大细胞至关重要： LT?? R 信号传导产生炎症介质，促进 LV 和 HEV 的快速发育。研究 B 细胞是否是 LN 肥大所需的膜 LT 的来源，以及 LT 如何产生与 LIGHT 配合放大 HEV 激活并促进 LV/HEV 内皮细胞生长。 1，我们将通过确定哪些细胞是LIGHT来研究LIGHT如何在细胞水平上介导LN肥大 LN 肥大期间产生光并对其作出反应所需的物质我们将测试朗格汉斯细胞是否存在。是 LN 肥大所必需的光产生细胞，我们还将鉴定光反应细胞，根据我们的初步数据，我们将其捕获为肥大细胞。在目标 2 中，我们将研究光如何发挥作用。在分子水平上介导 LN 肥大我们将定义其分子机制。 LIGHT 通过肥大细胞激活和 TNF-¿ 直接和/或间接调节 LV/HEV 内皮细胞我们还将研究 LIGHT 和 TNF-¿早期 LV/HEV 激活的坐标在目标 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 肥大期间是否以及如何合作在目标 4 中，我们将确定。光介导的淋巴结肥大在肿瘤免疫中的作用我们将定义其作用。光介导的（淋巴）血管生成在抗肿瘤 T 细胞启动中的作用并探索其治疗潜力使用 Ad-LIGHT 作为佐剂增强（淋巴）血管生成和 DC/T 细胞迁移，以改善总之，我们的研究将阐明驱动 LN 的细胞和分子机制。炎症反应引起的肥大，以及检查光介导的 DC 迁移的作用开发功能性抗肿瘤免疫反应和更有效的疫苗。 1