Examining the role of IFN-g+IL-17+ pathogenic Th17 cells in severe ocular allergy

检查 IFN-g IL-17 致病性 Th17 细胞在严重眼部过敏中的作用

• 批准号: 9272401
• 负责人: Nancy J Reyes
• 金额: $ 2.53万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-10-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272401
• 关键词: Adoptive Transfer; Adrenal Cortex Hormones; Adverse effects; Adverse event; Affect; Allergic Conjunctivitis; Animal Model; Anterior; Antibodies; Antihistamines; Area; Blepharitis; Cataract; Cells; Chronic; Clinical; Cornea; Data; Development; Disease; Elastases; Etiology; Frequencies; Giant Papillary Conjunctivitis; Goals; Hypersensitivity; IgE; Immunologics; Impaired wound healing; In Vitro; Infiltration; Inflammation; Injection of therapeutic agent; Interferon Type II; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Lead; Measures; Mediating; Medical; Modeling; Mus; Neutrophil Infiltration; Pathogenesis; Pathogenicity; Pathology; Patients; Peroxidases; Physiologic Intraocular Pressure; Play; Population; Production; Recruitment Activity; Role; Source; Symptoms; T-Lymphocyte Subsets; Testing; Vernal Keratoconjunctivitis; Vision; base; conjunctiva; cytokine; expectation; experimental study; interleukin-23; leukocyte activation; meibomian gland; mouse model; neutrophil; novel; novel therapeutics; outcome forecast; public health relevance; research study; secondary infection

DESCRIPTION (provided by applicant): Ocular allergy ranges from mild (i.e. seasonal and perennial allergic conjunctivitis (SAC and PAC, respectively)) to severe (i.e. atopic and vernal keratoconjunctivitis (AKC and VKC, respectively)). Current established models of ocular allergy predominantly mimic the mild forms; however, our lab has developed a novel mouse model that mimics more severe disease. Ocular allergy is classically a T helper (Th) 2-mediated disease; however, other Th cytokines, such as IFN-γ and IL-17, have been detected in AKC and VKC patients. While this suggests that Th1 and Th17 may be involved in severe ocular allergy, the cells responsible for the production of these cytokines have not been determined. My central hypothesis is that pathogenic IFN-γ+IL-17+ Th17 cells play a key role in the imunopathogenesis of severe ocular allergy, and they accomplish this via the recruitment of neutrophils. I have preliminary data comparing our model of severe ocular allergy with a model of mild allergy. My preliminary data demonstrates that mice with severe ocular allergy developed severe clinical manifestations consistent with what is seen in patients with AKC and VKC, specifically: white stringy discharge, anterior blepharitis, meibomitis, and corneal epitheliopathy, all of which are absent in the mild model. In addition, mice with severe ocular allergy have higher frequencies of pathogenic IFN-γ+IL-17+ Th17 cells compared to mice with mild disease. Interestingly, increased neutrophils were only detected in the conjunctiva of mice with severe ocular allergy, which is important because Th17 cells play a key role in neutrophil recruitment/activation. Thus, my preliminary data suggests that pathogenic IFN- γ+IL-17+ Th17 cells are important in the immunopathogenesis of severe ocular allergy, and may be doing so via recruitment and activation of effector neutrophils. I will test this with two aims. In my firstaim I will determine the role pathogenic IFN-γ+IL-17+ Th17 cells play in severe ocular allergy by depleting this population using anti- IL-23 and assessing how it affects the development of severe disease. In another experiment, I will also generate pathogenic IFN-γ+IL-17+ Th17 cells in vitro and determine if severe ocular allergy develops after adoptive transfer. In my second aim I will evaluate the role of IL-17-induced neutrophil infiltration into the conjunctiva in the pathogenicity of severe ocular allergy. I will do so by depleting neutrophils using anti-Ly6G and determining how severe ocular allergy is affected. In a subsequent experiment, I plan to test whether local transfer of neutrophils (via subconjunctival injection) can induce severe disease in the allergy setting. In summary, by the completion of these studies, my expectation is to have an understanding of the role of pathogenic IFN-γ+IL-17+ Th17 cells in severe ocular allergy. The successful completion of these studies has the potential to lead to creation of new therapies for this vision-threatening disease.

描述（由申请方提供）：眼部过敏的范围从轻度（即季节性和常年性过敏性结膜炎（分别为SAC和PAC））到重度（即特应性和春季角结膜炎（分别为AKC和VKC））。目前建立的眼过敏模型主要模拟轻度形式;然而，我们的实验室已经开发出一种新的小鼠模型，模拟更严重的疾病。眼部变态反应通常是辅助性T细胞（Th）2介导的疾病;然而，在AKC和VKC患者中检测到其他Th细胞因子，如IFN-γ和IL-17。虽然这表明Th 1和Th 17可能参与严重的眼部变态反应，但负责产生这些细胞因子的细胞尚未确定。我的中心假设是，致病性IFN-γ+IL-17+ Th 17细胞在严重眼部变态反应的免疫发病机制中起关键作用，并且它们通过募集中性粒细胞来实现这一点。我有初步的数据比较我们的模型严重眼过敏与模型轻度过敏。我的初步数据表明，患有严重眼部过敏的小鼠出现了与AKC和VKC患者一致的严重临床表现，特别是：白色线状分泌物、前睑缘炎、睑板炎和角膜上皮病，所有这些在轻度模型中均不存在。此外，与患有轻度疾病的小鼠相比，患有严重眼部变态反应的小鼠具有更高频率的致病性IFN-γ+IL-17+ Th 17细胞。有趣的是，仅在患有严重眼部过敏的小鼠的结膜中检测到增加的中性粒细胞，这是重要的，因为Th 17细胞在中性粒细胞募集/激活中起关键作用。因此，我的初步数据表明，致病性IFN- γ+IL-17+ Th 17细胞在严重眼部变态反应的免疫发病机制中是重要的，并且可能通过募集和激活效应中性粒细胞来实现。我将用两个目标来检验这一点。在我的第一个阶段，我将确定致病性IFN-γ+IL-17+ Th 17细胞在严重的眼部过敏中的作用，通过使用抗IL-23消除这一群体并评估它如何影响严重疾病的发展。在另一个实验中，我还将在体外产生致病性IFN-γ+IL-17+ Th 17细胞，并确定过继转移后是否会发生严重的眼部过敏。在我的第二个目标中，我将评估IL-17诱导的中性粒细胞浸润到结膜中在严重眼部过敏的致病性中的作用。我将通过使用抗Ly 6 G耗尽中性粒细胞并确定眼部过敏的严重程度来进行。在随后的实验中，我计划测试中性粒细胞的局部转移（通过结膜下注射）是否会在过敏环境中诱导严重的疾病。总之，通过这些研究的完成，我的期望是了解致病性IFN-γ+IL-17+ Th 17细胞在严重眼部变态反应中的作用。这些研究的成功完成有可能为这种威胁视力的疾病创造新的疗法。