Choroidal Gamma Delta T Cells as Novel Regulators of RPE Degeneration

脉络膜 Gamma Delta T 细胞作为 RPE 变性的新型调节剂

基本信息

批准号：
10005361
负责人：
JIYANG CAI
金额：
$ 42.05万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005361
关键词：
Adoptive Transfer Age related macular degeneration Animals Antigens Aryl Hydrocarbon Receptor Blood-Retinal Barrier Cell physiology Cell surface Cells Cellular Immunity Cholesterol Choroid Chronic Clonal Expansion Coculture Techniques Degenerative Disorder Dependence Development Diabetic Retinopathy Diet Dietary Intervention Dietary Phytochemical Dietary Supplementation Disease Disease susceptibility Epidermis Epithelial Epithelial Cells Epithelium Event Fatty acid glycerol esters Flow Cytometry Gene Expression Growth Factor Homeostasis Immune Immune response Immunologic Surveillance Indoles Inflammation Inflammatory Inflammatory Response Innate Immune Response Interleukin-1 Interleukin-10 Interleukin-17 Interleukin-4 Intervention Intestinal Mucosa Knock-out Knockout Mice Ligation Literature Lymphocyte Lymphoid Cell Measures Microglia Modeling Monitor Mus Natural Immunity Nuclear Orphan Receptor Organ Outcome Pathologic Pathology Pathway interactions Patients Phenotype Phytochemical Population Production Property Publishing RNA analysis Recovery Reporting Resolution Retina Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Role Severities Site Sterility Structure of retinal pigment epithelium Supplementation Synthetic Diet System T cell therapy T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte Testing Therapeutic Tissues Toxic effect Tretinoin Vascular blood supply age related base conditional knockout cytokine epithelial injury immune activation immune function immunoregulation innovation interleukin-23 intraepithelial macrophage neurosensory novel pathogen prevent protective effect recruit repaired response retinal damage sodium iodate transcriptome transcriptome sequencing γδ T cells

项目摘要

PROJECT SUMMARY Degeneration of the retinal pigment epithelium (RPE) is a pathological event commonly seen in various retinal diseases such as age-related macular degeneration and retinitis pigmentosa. The RPE is part of the outer blood retinal barrier that separates choroidal blood supply from the neurosensory retina. RPE injury activates retinal and choroidal compartment immune cells. The responses can either promote repair and recovery of the epithelium, or cause further tissue damage and immune pathology. Mechanisms controlling inflammation and immune functions in the outer retina and choroid are largely unclear. Clarifying the interactions between the RPE and immune cells is crucial for a better understanding of disease development and progression.  T cells are a group of unconventional, innate-like lymphocytes with potent effects on cell-mediated immunity near the epithelial barrier. We found that choroidal  T cells have novel protective functions in response to RPE injury through their functional interactions with the RPE.  T cell-deficient mice show increased sensitivity to sodium iodate-induced RPE damage and retinal toxicity; adoptive transfer of  T cells reverses this sensitization. Immune regulatory cytokines, such as interleukins 4, 10 and 17, are produced by choroidal  T cells via aryl hydrocarbon receptor (AhR)-dependent mechanisms. Accordingly, adoptive transfer of AhR- deficient  T cells is not protective against RPE injury in the sodium iodate model. Based on the findings from our published and preliminary studies, in the current proposal we hypothesize that choroidal  T lymphocytes regulate tissue homeostasis in the outer retina via AhR-dependent mechanisms. Three specific aims will be used to test the hypothesis. Aim 1 is to characterize choroidal  T cell function during chronic RPE degeneration conditions. Aim 2 is to determine the mechanistic role of AhR in activation of choroidal  T cells and their production of regulatory cytokines. Aim 3 is to determine whether modulating AhR activity by dietary phytochemicals will influence the protective effects of choroidal  T cells against RPE degeneration. The results from the proposed studies will define whether enhancing choroidal  T cell function is potentially a novel interventional strategy for treating retinal diseases that involve RPE degeneration.

项目概要视网膜色素上皮（RPE）变性是各种视网膜中常见的病理事件。诸如年龄相关性黄斑变性和色素性视网膜炎等疾病，RPE 是外层的一部分。将脉络膜血液供应与神经感觉视网膜损伤分开的血视网膜屏障被激活。视网膜和脉络膜免疫细胞的反应可以促进修复和恢复。上皮细胞，或引起进一步的组织损伤和控制炎症和免疫病理学的机制。外视网膜和脉络膜的免疫功能在很大程度上尚不清楚。 RPE 和免疫细胞对于更好地了解疾病的发生和进展至关重要。细胞是一组非常规的、先天性的淋巴细胞，对细胞介导的免疫具有强大的作用我们发现脉络膜  T 细胞对 RPE 具有新的保护功能。  T 细胞缺陷小鼠表现出对 RPE 的功能性相互作用的敏感性增加。碘酸钠诱导的 RPE 损伤和  T 细胞的过继转移可逆转这一情况；免疫调节细胞因子，如白介素 4、10 和 17，由脉络膜  T 产生。细胞通过芳基碳氢化合物受体（AhR）依赖性机制，因此，AhR-的过继转移。根据碘酸钠模型的研究结果，缺乏  T 细胞不能防止 RPE 损伤。我们已发表的初步研究，在当前的提案中，我们采用了脉络膜  T 淋巴细胞通过 AhR 依赖性机制调节外视网膜组织稳态。具体目标将用于检验假设。目标 1 是表征脉络膜  T 细胞功能。目标 2 是确定 AhR 在激活 RPE 中的机制作用。目的 3 是确定脉络膜  T 细胞及其调节性细胞因子的产生是否具有调节作用。膳食植物化学物质的 AhR 活性将影响脉络膜  T 细胞对 RPE 的保护作用拟议研究的结果将确定是否增强脉络膜  T 细胞功能。可能是一种治疗涉及 RPE 变性的视网膜疾病的新型介入策略。