Corneal Lymphatics & Adaptive Immunity

角膜淋巴管

• 批准号: 8204539
• 负责人: DANIEL J CARR
• 金额: $ 36.79万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204539
• 关键词: Acute; Address; Antibodies; Antigens; Attenuated; Blood; CD8B1 gene; Cells; Cornea; Development; Effector Cell; Generations; Goals; Herpesvirus 1; Herpetic Keratitis; Immune; Immune response; Infection; Inflammation Mediators; Inflammatory; Keratitis; Keratoplasty; Lead; Leukocyte Trafficking; Lymphangiogenesis; Lymphatic; Lymphatic vessel; Maintenance; Mediating; Monitor; Mus; Ocular Pathology; Pathogenesis; Pathology; Pathway interactions; Process; Production; Relative (related person); Role; Severities; T cell response; Testing; Therapeutic Intervention; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Viral; Virus; Visual; adaptive immunity; chemokine; corneal epithelium; cytokine; driving force; lymph nodes; macrophage; monocyte; mouse model; neovascularization; response; trafficking; treatment strategy

Neovascularization in the normally avascular cornea can lead to a compromised visual axis. Within the term "neovascularization" is a blood component referred to as hemangiogenesis and a lymphatic component referred to as lymphangiogenesis. Relative to herpes simplex virus type 1 (HSV-1) infection, only hemangiogenesis has been investigated. Recently, we have initiated a study on lymphangiogenesis following corneal infection with HSV-1 and discovered this process precedes hemangiogenesis. More importantly, we have discovered the genesis of lymphatic vessels in the cornea proper in response to HSV-1 infection operates thru a unique pathway distinct from what has been described following corneal transplantation. Specifically, we have found a robust vascular endothelial growth factor (VEGF) A response by corneal epithelium infected with HSV-1 elicits lymphangiogenesis thru a VEGF receptor 2 (VEGFR2)-mediated pathway. This process is independent of VEGF C, VEGF receptor 3, or monocytes/macrophages. We have also found the newly created lymphatic vessels are capable of transporting soluble antigen to the draining lymph node independent of hemangiogenesis. However, what remains unknown is the contribution of the newly created lymphatic conduit to the host immune response within the draining lymph node as well as other inflammatory mediators that contribute to corneal lymphangiogenesis. We hypothesize lymphatic vessel development driven principally by VEGF A and contributing pro-inflammatory molecules generated locally in response to infection are critical for the induction of the adaptive immune response found in the draining lymph node reflected by the severity in the development of herpetic stromal keratitis of HSV-1 infected mice. To address this hypothesis, two specific aims are proposed: Specific aim 1 will address the impact of viral replication and pro- inflammatory cytokine expression on corneal lymphangiogenesis following HSV-1 infection. In addition, trafficking of leukocyte subpopulations and antigen will be monitored as well. Specific aim 2 will address the significance of lymphangiogenesis relative to the genesis of the adaptive immune response in the draining lymph node and development of stromal keratitis following HSV-1 infection. It will further address the role of virus-induced VEGF A production on the production of CD4+ and CD8+ T effector cells that contribute in viral surveillance and corneal pathogenesis. It is anticipated in accomplishing these goals, we will eludicate the contribution of pro-lymphangiogenesis factors in the generation of the adaptive immune response critical for the ocular pathology that includes the debilitating and sometimes blinding stromal keratitis.

正常血管角膜中的新血管形成会导致视觉轴的受损。 在“新血管化”一词中，是一种血管生成和 淋巴成分称为淋巴管生成。相对于单纯疱疹病毒类型 1（HSV-1）感染，仅研究了血管生成。最近，我们发起了 在用HSV-1感染角膜后淋巴管生成的研究并发现了这一过程 先于血管生成。更重要的是，我们发现了淋巴的起源 响应于HSV-1感染的角膜中的血管通过独特的途径运行 与角膜移植后描述的不同。具体来说，我们有 发现稳健的血管内皮生长因子（VEGF）是角膜上皮的反应 通过VEGF受体2（VEGFR2）介导的HSV-1感染淋巴管生成 路径。此过程与VEGF C，VEGF受体3或 单核细胞/巨噬细胞。我们还发现新创建的淋巴管是 能够将可溶性抗原传输到独立于排水淋巴结 血管生成。但是，未知的是新创建的贡献 淋巴管淋巴管在排水淋巴结和其他内的宿主免疫反应 有助于角膜淋巴管生成的炎症介质。我们假设 淋巴管发育主要由VEGF A驱动，并促进促炎 响应感染的本地产生的分子对于自适应的诱导至关重要 发育中严重程度反射的排水淋巴结中发现的免疫反应 HSV-1感染小鼠的疱疹性基质角膜炎。为了解决这一假设，两个特定的 提出了目的：具体目标1将解决病毒复制和促进的影响 HSV-1感染后角膜淋巴管生成的炎性细胞因子表达。在 此外，还将监测白细胞亚群和抗原的贩运。具体的 AIM 2将解决相对于自适应起源的淋巴管生成的重要性 在排水淋巴结中的免疫反应和基质角膜炎的发育之后 HSV-1感染。它将进一步解决病毒引起的VEGF生产的作用 在病毒监测和角膜中产生贡献的CD4+和CD8+ T效应细胞 发病。预计实现这些目标时，我们将避免 在自适应免疫反应的产生中，促淋巴管生成因子至关重要 眼科病理，包括使人衰弱，有时甚至是盲目的基质角膜炎。