Corneal Lymphatics & Adaptive Immunity

角膜淋巴管

• 批准号: 8922184
• 负责人: DANIEL J CARR
• 金额: $ 15.51万
• 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/8922184
• 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.

正常无血管角膜中的新血管形成可导致视轴受损。 在术语“新血管形成”内，是称为血管生成的血液成分， 称为淋巴管生成的淋巴成分。相对于单纯疱疹病毒型 1（HSV-1）感染，仅研究了血管生成。最近，我们发起了一项 HSV-1角膜感染后淋巴管生成的研究，发现了这一过程 先于血管生成更重要的是，我们发现了淋巴细胞的起源 角膜中的血管对HSV-1感染的反应是通过一个独特的途径进行的 与角膜移植后所描述的不同。具体来说，我们有 发现角膜上皮对血管内皮生长因子（VEGF）A有强烈的反应， HSV-1感染通过VEGF受体2（VEGFR 2）介导的淋巴管生成 通路这一过程不依赖于VEGF C、VEGF受体3或 单核细胞/巨噬细胞。我们还发现新产生的淋巴管 能够将可溶性抗原转运至引流淋巴结， 血管生成然而，仍然未知的是新创建的 淋巴管到引流淋巴结内的宿主免疫应答以及其他 导致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， 局部产生的分子对感染的反应是诱导适应性细胞的关键。 引流淋巴结中发现的免疫应答，反映在发展的严重程度上 HSV-1感染小鼠的疱疹性角膜基质炎。为了解决这个问题，两个具体的 具体目标1将解决病毒复制和亲病毒的影响， HSV-1感染后角膜淋巴管生成中炎性细胞因子表达在 此外，还将监测白细胞亚群和抗原的运输。具体 目的2将阐述淋巴管生成相对于适应性淋巴瘤发生的重要性。 引流淋巴结的免疫应答与基质角膜炎的发生 HSV-1感染。它将进一步阐明病毒诱导的VEGFA产生对细胞增殖的作用。 产生CD 4+和CD 8 + T效应细胞，有助于病毒监视和角膜 发病机制预计在实现这些目标的过程中，我们将回避 促淋巴管生成因子在产生适应性免疫应答中的作用， 包括使人衰弱有时使人失明的角膜基质炎的眼部病理学。