The role of plasmacytoid dendritic cells in corneal immunity

浆细胞样树突状细胞在角膜免疫中的作用

基本信息

批准号：
9329957
负责人：
Pedram Hamrah
金额：
$ 11.11万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9329957
关键词：
Address Affect Animals Anti-Inflammatory Agents Anti-inflammatory Antigens Antiviral resistance Area Autoimmune Diseases Autoimmune Process Automobile Driving Blindness Blocking Antibodies Blood Vessels Bone Marrow CD4 Positive T Lymphocytes Cell Adhesion Molecules Cell Communication Cells Chimera organism Cornea Corneal Diseases Critical Pathways Data Dendritic Cells Destinations Disease Disease Outcome Eye diseases Harvest Health Herpetic Keratitis Homing Host Defense Image Immune Immune response Immune system Immunity Immunotherapy Infection Inflammation Inflammatory Integrins Interferon Type I Interferons Interleukin-6 Intervention Keratitis Kinetics Label Leukocytes Life Link Mediating Modeling Molecular Molecular Target Mus Organ Participant Pathway interactions Peripheral Pharmaceutical Preparations Phenotype Play Population Production Productivity Property Proteins Recombinants Regulatory T-Lymphocyte Resolution Role Selectins Signal Transduction Simplexvirus Source T cell response T-Lymphocyte TLR7 gene TLR9 gene TNF gene Testing Tissues Toll-like receptors Transgenic Mice Transgenic Organisms Up-Regulation Viral Virus Virus Diseases Vision Visual impairment Work adaptive immunity antiviral immunity base cell motility chemokine corneal scar effective therapy fighting in vivo innovation intravital microscopy lymph nodes macrophage migration multi-photon novel novel therapeutics pathogen prevent research study trafficking

项目摘要

DESCRIPTION (provided by applicant): Plasmacytoid dendritic cells (pDC), a distinct type of bone marrow-derived cell, play an important role in linking innate and adaptive immune responses. pDC are pivotal in the first line of defense against viral infections through recognitio of viruses by toll-like receptors as well as their ability to produce large amounts of type I interferons (IFN). In preliminary studies, we have discovered a novel population of resident pDC in the cornea. In vivo pDC depletion in our preliminary studies demonstrate that pDC are the major source of IFN-a in the cornea and play a protective role in the host defense in herpes simplex keratitis (HSK). Thus our results suggest that pDC are key participants in fighting viral keratitis, while preserving vision. Identifying specific functions of pDC in HSK and understanding the critical pathways of pDC and T cell migration in the cornea may provide new molecular targets for pharmacological intervention through immunotherapy. However, defining organ- and cell-specific molecular migratory mechanisms is critical, in order to inhibit cell subsets driving disease, without affecting leukocytes required for protective immunity. To address these questions, we have developed a new multiphoton intravital microscopy (MP-IVM) model to study pDC in intact corneas of living mice. This imaging approach uses transgenic mice, with fluorescent pDC, and fluorescent viruses, and will visualize pDC and viruses at subcellular resolution in living animals, allowing us to study their interaction with surrounding cells. Based on preliminary work and that up-regulation of organ-specific combination of vascular adhesion molecules and chemokines regulate pDC and T cell recruitment to the cornea and subsequent migration of pDC from the cornea in inflammation and infection. We further hypothesize that pDC are protective to the cornea in HSK through local corneal IFN-? and TNF-? production and migrate to distinct areas of the dLN after activation in HSK, where they mediate differentiation pathways of CD4+ T cells to T regulatory or T helper (Th)17 cells through IFN-? and IL-6 production. pDC will be studied to investigate the traffic signals that guide them to normal and inflamed corneas and will be used to address the following two specific aims: 1.) To characterize corneal pDC and dissect the molecular mechanisms that mediate their recruitment and egress during inflammation; 2.) To characterize corneal pDC and dissect the molecular mechanisms that mediate their recruitment and egress during inflammation. Identification of these critical pathways of cell migration to and from the cornea will provide new and highly specific molecular targets for pharmacological intervention in inflammatory, infectious, alloimmune and autoimmune diseases. Few effective anti-inflammatory drugs have emerged over the last decades in the ophthalmic field and an urgent need for new drugs exists. HSK is a leading cause of blindness. Effective therapy for HSK would significantly reduce visual impairment, increase productivity, and reduce the burden of treating HSK.

描述（由申请人提供）：浆细胞类动物树突状细胞（PDC）是一种独特的骨髓衍生细胞，在连接先天和适应性免疫反应方面起着重要作用。 PDC是通过Toll样受体识别病毒识别病毒感染的第一道防御病毒感染的关键，以及它们产生大量I型干扰素（IFN）的能力。在初步研究中，我们发现了角膜中的新居民PDC人群。在我们的初步研究中，体内PDC的耗竭表明，PDC是角膜中IFN-A的主要来源，并且在单纯疱疹角膜炎（HSK）中在宿主防御中起保护作用。因此，我们的结果表明，PDC是对抗病毒性角膜炎的关键参与者，同时保持视力。确定PDC在HSK中的特定功能并了解角膜中PDC和T细胞迁移的关键途径可能为通过免疫疗法提供了新的分子靶标，以进行药理干预。但是，为了抑制驱动疾病的细胞子群，定义器官和细胞特异性分子迁移机制至关重要，而不会影响保护性免疫所需的白细胞。为了解决这些问题，我们开发了一种新的多极子弹刻体显微镜（MP-IVM）模型，以研究活小鼠完整角膜的PDC。这种成像方法使用转基因小鼠，带有荧光PDC和荧光病毒，并将在活动物的亚细胞分辨率下可视化PDC和病毒，从而使我们能够研究它们与周围细胞的相互作用。基于初步工作以及血管粘附分子和趋化因子的器官特异性组合的上调调节PDC和T细胞募集到角膜以及随后在炎症和感染中PDC从角膜中迁移。我们进一步假设PDC通过局部角膜IFN-可以保护HSK的角膜？和tnf-？在HSK中激活后，生产并迁移到DLN的不同区域，在那里它们通过IFN-介导CD4+ T细胞的分化途径为T调节或T助手（Th）17个细胞。和IL-6生产。将研究PDC以调查引导它们达到正常和发炎的角膜的交通信号，并将用于解决以下两个特定目的：1。）表征角膜PDC并剖析介导其在炎症过程中介导其募集和出口的分子机制； 2.）表征角膜PDC并剖析炎症过程中介导其募集和出口的分子机制。鉴定这些细胞迁移到角膜的关键途径将为炎症，传染性，同种免疫和自身免疫性疾病提供新的，高度特定的分子靶标。在过去的几十年中，在眼科领域中，很少有有效的抗炎药出现，并且迫切需要新药。 HSK是失明的主要原因。 HSK的有效治疗将大大降低视觉障碍，提高生产率并减轻治疗HSK的负担。