Impact of tissue resident memory T cells on the neuro-immunepathophysiology 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：
10804810
负责人：
Alexander Skorput
金额：
--
依托单位：
DARTMOUTH-HITCHCOCK CLINIC
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：
2023-03-08 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10804810
关键词：
Acute Address Anterior Anti-Inflammatory Agents Antigens Applications Grants Cell Communication Cells Chronic Circulation Clinical Cornea Data Development Dry Eye Syndromes Environment Exhibits Exposure to Eye Eye Infections Eye diseases Feedback Functional disorder Funding Herpesvirus 1 Human Hypersensitivity Immune Immunologics Inflammation Inflammatory Investigation Knowledge Laboratories Laboratory mice Mediating Mediator Modeling Mus Nervous System Neurogenic Inflammation Neuroimmune Neuroimmunomodulation Neuropeptides Nociceptors Pain Patients Peripheral Phenotype Population Pre-Clinical Model Recurrence Research Research Personnel Research Project Grants Rodent Rodent Model Sensory Shapes Skin Substance P T memory cell T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets TNF gene Testing Tissues Vaccination Viral Virus Diseases Work clinically relevant cytokine experience eye dryness genetic approach in vivo innovation insight multidisciplinary neuroimmunology neuroinflammation novel ocular pain ocular surface pathogen pathogen exposure pathogenic virus pre-clinical receptor 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 interaction 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. These studies will gain critical insights into neuro-immune mechanisms that drive the pathophysiology of anterior eye disease, and show how prior viral infection shapes the manifestation of subsequent neuro-inflammation. This work will inform innovative avenues for the treatment of ocular pain and inflammation, and bear broad impact in the field of neuro-immunology through a first-ever investigation of TRM interactions with the sensory nervous system.

抽象的 T细胞是抗炎治疗持续性眼疼痛的主要临床靶标眼部疾病，例如干眼症，但T细胞子群的鉴定驱动了前部的病理生理学眼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。建立这些组织居民的记忆T细胞（TRM）需要病原体暴露或疫苗接种，并且因为我们在不自然清洁的环境中容纳实验室啮齿动物，所以它们的暴露极有限致病。缺乏免疫学经验，无法使用额外的啮齿动物模型来调查 TRM在前眼病的神经免疫机制中的影响，以及眼部炎症和疼痛中的TRM和伤害感受器仍然是知识的紧迫差距。我们建议通过临床相关的眼病原体来解决被感染的小鼠的差距，以建立“人类人群喜欢“眼睛中的trm，可以专门针对激活或耗尽。使用这种啮齿动物模型，我们将调节前眼中TRM和/或伤害感受器的活性/存在，以测试中心假设 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。这些研究将获得对驱动神经免疫机制的关键见解前眼病的病理生理学，并显示先前的病毒感染如何塑造随后的神经炎症。这项工作将为您的创新途径提供有关眼痛和治疗的途径通过对TRM进行的首次研究，炎症并在神经免疫学领域产生广泛的影响与感觉神经系统的相互作用。