Dermal Lymphatic Transport and Cutaneous Immune Balance

真皮淋巴运输和皮肤免疫平衡

• 批准号: 10339645
• 负责人: Amanda W. Lund
• 金额: $ 44.02万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339645
• 关键词: Acute; Antigen Presentation; Antigens; Autoimmunity; Automobile Driving; Biology; CD8-Positive T-Lymphocytes; Cells; Chronic; Clinical; Communication; Cutaneous; Data; Dendritic Cells; Dependence; Dermal; Dermatopathology; Dermis; Endothelium; Equilibrium; Exhibits; Functional disorder; Genetic; Goals; Hematopoietic; Homeostasis; Immune; Immune response; Immunity; Immunologic Surveillance; Immunology procedure; Immunotherapeutic agent; Impairment; Inflammation; Inflammatory; Intercellular Fluid; KDR gene; Knockout Mice; Knowledge; Leukocytes; Ligands; Link; Liquid substance; Lymph; Lymphatic; Lymphatic Capillaries; Lymphatic Endothelial Cells; Lymphatic Endothelium; Malignant Neoplasms; Mediating; Molecular; Mus; Pathway interactions; Phenotype; Physiological; Physiology; Publishing; Resolution; Role; Route; Sentinel; Signal Transduction; Skin; Source; Structure of germinal center of lymph node; System; T cell response; Testing; Therapeutic; Translating; VEGFA gene; Viral; Virion; Virus; Virus Diseases; Work; adaptive immune response; adaptive immunity; cell motility; combat; design; draining lymph node; fluid flow; high resolution imaging; immune activation; immune checkpoint blockade; immunoreaction; in vivo; insight; interstitial; lymph nodes; lymphatic circulation; lymphatic vasculature; lymphatic vessel; migration; neoplasm immunotherapy; novel; novel therapeutics; pathogen; pressure; response; tool; transcriptomics; treatment response; vaccine development; vaccine immunogenicity; vaccine immunotherapy; vaccine response

PROJECT SUMMARY While we have established a tremendous amount of knowledge interrogating intrinsic leukocyte biology to inform a breadth of immunotherapeutic approaches, more can be done to understand how cutaneous immune responses are regulated and to translate that understanding into therapies that combat cutaneous immune imbalance (autoimmunity, chronic inflammation, malignancies). The goal of this proposal is to elucidate mechanisms of lymphatic transport that contribute to local inflammation and adaptive immune induction to provide novel insight into how we may tune immune responses in vivo. Our published and preliminary work establishes the dermal lymphatic vasculature as a necessary route for both immune activation (ON) and immune resolution (OFF) signals. Further, we have demonstrated that dermal lymphatic vessels remodel their inter- endothelial junctions (termed ‘zippering’) with functional consequences for pathogen dissemination and immune induction. Whether these same mechanisms are activated across cutaneous immune phenotypes and how changes in lymphatic transport directly impact immunity remains unknown. In this proposal we test the hypothesis that dermal lymphatic vessels exhibit active, context-dependent functional remodeling to coordinate cutaneous immune surveillance. This hypothesis will be tested along two aims: (1) we will evaluate the crosstalk between lymphatic transport and the interstitial, inflammatory microenvironment in skin; (2) determine the functional significance of lymphatic zippering in adaptive immune activation in draining lymph nodes. To complete these aims, we couple genetic tools with robust immunological assays and high-resolution imaging to resolve the systems-level interactions between skin and draining lymph nodes in vivo as a function of the connecting lymphatic vasculature. We propose that lymphatic vessel transport is a poorly understood but active determinant of cutaneous immune responses and that identification of specific molecular mechanisms that regulate their function provides novel therapeutic opportunities to tune immunity up or down. Our work will not only develop our physiological understanding of lymphatic transport and its contribution to immunity but further suggest novel design principles for how to manage immunological reactions in skin. In this way our work may help to inform clinical vaccine development and immunotherapy and may identify targets to maintain tolerance during homeostasis and in response to therapy (e.g. immune checkpoint blockade).

项目摘要 虽然我们已经建立了大量的知识来审问内在的白细胞生物学，以告知 一系列免疫治疗方法，可以做更多的事情来了解皮肤免疫 对反应受到调节，并将这些理解转化为对抗皮肤免疫的疗法 失衡（自身免疫，慢性炎症，恶性肿瘤）。该提议的目的是阐明 淋巴运输机制，导致局部炎症和适应性免疫学诱导 提供有关我们如何在体内调节免疫反应的新见解。我们出版的初步工作 建立真皮淋巴脉管系统，作为免疫激活（ON）和免疫的必要途径 分辨率（OFF）信号。此外，我们已经证明了皮肤淋巴视频重塑其间 内皮连接（称为“拉链”），对病原体传播和免疫产生功能后果 就职。这些相同的机制是否在皮肤免疫表型中激活 淋巴运输的变化直接影响免疫力仍然未知。在此提案中，我们测试了 假设真皮淋巴管暴露于有效的，上下文依赖性功能重塑以坐标 皮肤免疫监视。该假设将以两个目的进行检验：（1）我们将评估串扰 在淋巴运输和皮肤中的炎性微环境之间； （2）确定 淋巴作用在排水淋巴结中自适应免疫反应中的功能显着性。到 完成这些目的，我们将遗传工具与强大的免疫学测定和高分辨率成像相结合 解决体内皮肤和排水淋巴结之间的系统级相互作用 连接淋巴脉管系统。我们建议淋巴管的运输知之甚少，但活跃 皮肤免疫反应的决定因素，并鉴定出特定分子机制 调节其功能提供了新型的治疗机会，可以调整或向下调整免疫力。我们的工作不会 仅发展我们对淋巴运输及其对免疫的贡献的物理理解，但进一步 提出有关如何管理皮肤免疫反应的新型设计原理。这样我们的工作可能 帮助告知临床疫苗开发和免疫疗法，并可能识别靶标以保持耐受性 在体内稳态和响应治疗期间（例如免疫检查点封锁）。