Impact of tissue resident memory T cells on the neuro-immune pathophysiology of anterior eye disease

组织驻留记忆 T 细胞对前眼疾病神经免疫病理生理学的影响

基本信息

批准号：
10556857
负责人：
Alexander Skorput
金额：
$ 56.65万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2023-02-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10556857
关键词：
Adaptive Immune System Address Animal Model Animals Anterior Anti-Inflammatory Agents Antigens Applications Grants Automobile Driving Blood CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cell physiology Cells Chronic Circulation Clinical Cornea Data Desiccation Development Disease Disease model Dry Eye Syndromes Environment Exhibits Exposure to Eye Eye Infections Eye diseases Functional disorder Funding Genital Genitalia Herpesvirus 1 Homeostasis Human Hypersensitivity Immune Immunologic Memory Immunologics Incidence Inflammation Inflammatory Investigation Knowledge Laboratories Laboratory mice Mediator Memory Modeling Mucous Membrane Mus Nervous System Neurogenic Inflammation Neuroimmune Neuroimmunomodulation Neuropeptides Nociceptors Pain Pathology Patients Peripheral Phenotype Population Pre-Clinical Model Predisposition Prevalence Prevention Productivity Quality of life Research Research Personnel Research Project Grants Rodent Rodent Model Sensory Shapes Skin Stress Substance P T memory cell T-Cell Activation T-Cell Depletion T-Lymphocyte T-Lymphocyte Subsets TNF gene Testing Tissues United States Vaccination Virus Virus Diseases Visual Acuity Work clinically relevant cytokine economic impact experience eye dryness genetic approach in vivo innovation insight mouse model multidisciplinary neuroimmunology neuroinflammation novel ocular pain ocular surface pathogen pathogen exposure pre-clinical tissue resident memory T cell

项目摘要

ABSTRACT T cells are major clinical targets for anti-inflammatory treatment of persistent ocular pain induced by anterior eye diseases such as dry eye, yet identification of which T cell subsets drive the pathophysiology of anterior eye disease remains a topic of intensive preclinical investigation. Emerging data shows that a relatively recently discovered pro-inflammatory subset of T cells that rarely re-enter circulation dominate the T cell niche on the ocular surface of humans but are almost nonexistent in preclinical models of dry eye disease. Establishment of these tissue resident memory T cells (TRM) in the eye requires pathogen exposure or vaccination, and because we house laboratory rodents in unnaturally clean environments, they have extremely limited exposure to pathogens. This lack of immunologic experience has precluded the use of extant rodent models to investigate the impact of TRM in neuro-immune mechanisms of anterior eye disease, and the potential interactions between TRM and nociceptors in ocular inflammation and pain remains a pressing gap in knowledge. We propose to address this gap by infecting mice with a clinically relevant ocular pathogen to establish a population of “human- like” TRM in the eye that can be specifically targeted for activation or depletion. Using this rodent model, we will modulate the activity/presence of TRM and/or nociceptors in the anterior eye to test the central hypothesis that TRM and nociceptors engage in bidirectional neuro-immune interactions that cause ocular pain and inflammation. Additionally, these animals will be used in a desiccating stress model of dry eye disease with and without depletion of resident (TRM), and/or circulating virus-specific CD8+ memory T cells, to determine the relative impact of these experience-dependent memory immune cell populations on dry eye pathophysiology. These studies will gain critical insights into neuro-immune mechanisms that drive the pathophysiology of anterior eye disease and determine how prior viral infection shapes the manifestation of subsequent neuro-inflammation. This work will inform innovative avenues for the treatment of human ocular pain and inflammation and bear broad impact for the field of neuro-immunology through first-ever investigation of TRM interactions with the sensory nervous system.

抽象的 T细胞是前眼引起的持续性眼疼痛的抗炎治疗的主要临床靶标诸如干眼症之类的疾病，但T细胞子集的鉴定驱动了前眼病理生理学疾病仍然是深入临床前研究的话题。新兴数据表明，一个相对近期发现了很少重新进入圆圈的T细胞的促炎子集主导着T细胞生态位人类的眼表面，但在干眼症的临床前模型中几乎不存在。建立这些组织居民记忆T细胞（TRM）需要病原体暴露或疫苗接种，因为我们在不自然清洁的环境中容纳实验室啮齿动物，它们的暴露量极为有限病原体。缺乏免疫学经验，无法使用额外的啮齿动物模型来研究 TRM在前眼病的神经免疫机制中的影响以及TRM之间的潜在相互作用眼部炎症和疼痛中的伤害感受器仍然是知识的紧迫差距。我们建议解决受感染的小鼠具有临床相关的眼病原体的差距，以建立“类人” TRM的群体在可以专门针对激活或耗竭的眼睛中。使用这种啮齿动物模型，我们将调整在前眼中TRM和/或伤害感受器的活性/存在，以测试TRM和伤害感受器从事双向神经免疫相互作用，引起眼部疼痛和炎症。此外，这些动物将在有或没有的干燥眼病的干燥胁迫模型中使用居民（TRM）和/或循环病毒特异性CD8+记忆T细胞的耗竭，以确定相对这些依赖经验的记忆免疫细胞群对干眼病理生理学的影响。这些研究将获得对驱动前眼病理生理学的神经免疫机制的关键见解疾病并确定先前的病毒感染如何塑造随后的神经炎症的表现。这项工作将为治疗人眼疼痛和感染的创新途径提供信息，并承受广泛通过首次研究TRM与感觉的影响，对神经免疫学领域的影响神经系统。