Antigen presentation to the adaptive immune system in the choroid contributes to ocular autoimmune disease

脉络膜中的适应性免疫系统的抗原呈递导致眼部自身免疫性疾病

• 批准号: 10740465
• 负责人: James Walsh
• 金额: $ 24.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740465
• 关键词: Adaptive Immune System; Adoptive Transfer; Affect; Anatomy; Anterior uveitis; Antigen Presentation; Antigen-Presenting Cells; Antigens; Aqueous Humor; Area; Arrestins; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; Benign; Blindness; Blood Vessels; CD4 Positive T Lymphocytes; CNS autoimmunity; CXCR6 gene; Cell Adhesion Molecules; Cells; Central Nervous System; Choroid; Circulation; Clinical; Data; Data Set; Development; Development Plans; Diagnostic tests; Disease; Doctor of Philosophy; Drainage procedure; Environment; Enzyme-Linked Immunosorbent Assay; Experimental Models; Eye; Eye diseases; Flow Cytometry; Funding; Future; Gene Expression Profile; Goals; Histologic; ICAM1 gene; Image; Immune; Immune response; Immune system; Immunity; Immunohistochemistry; Immunologic Surveillance; Immunology; Inflammation; Inflammatory; Institution; Knock-in; Knowledge; Learning; Lymphatic; Lymphocyte; Measures; Mediator; Medical; Medical Research; Memory; Meninges; Mentors; Mentorship; Methods; Modeling; Molecular; Mus; Nerve Degeneration; Neurosciences; Operative Surgical Procedures; Ophthalmology; Outcome; Ovalbumin; Papillary; Pathogenesis; Pathogenicity; Patient Care; Peripheral; Pharmaceutical Preparations; Play; Population; Principal Investigator; Process; Productivity; Recurrent disease; Research; Research Personnel; Retina; Role; Route; Scientist; Severities; Signal Transduction; Source; Structure of retinal pigment epithelium; Systemic Therapy; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Training; United States; Universities; Uveitis; Washington; Work; adaptive immune response; antigen-specific T cells; autoimmune uveitis; autoreactive T cell; axon injury; base; brain parenchyma; career; career development; cell behavior; cell motility; chemokine; chemokine receptor; clinical training; cytokine; differential expression; improved; in vivo imaging; intravital microscopy; knowledge base; migration; monocyte; multi-photon; novel; programs; research and development; response; skill acquisition; skills; targeted treatment; trafficking; vision science

Project summary: The overarching goal of this project is to develop the principal investigator (PI) into an independent clinician- scientist contributing to the field of ocular autoimmunity. The PI has obtained his PhD in neuroscience, exploring the roles of the adaptive immune system in axonal injury models. He has additional clinical training in ophthalmology and subspecialty training in uveitis and ocular immunology, which forms the basis for his medical practice in the Department of Ophthalmology and Visual Sciences at Washington University in St. Louis. The five-year career development plan outlined here will utilize a combination of didactic courses, individualized training from expert collaborators, and mentorship from established investigators to enhance his knowledge base, to learn new experimental models he can continue to use in his career, and to define the research questions on which he will base the start of his independent research program. By the end of this program, he will have acquired the skills necessary to become an independent investigator. His primary mentor is Rajendra Apte, MD PhD, an R01-funded investigator who has a longitudinal track record of training early-stage investigators that have gone on to productive independent careers. He is a preeminent scholar in the field of choroidal immunity and has a strong background as a clinician scientist that will be vital for helping the PI navigate the challenges involved in transitioning to an independent lab. Dr. Apte will be supported by Rachel Caspi, PhD, the world-leading expert in experimental autoimmune uveitis, Jonathan Kipnis, PhD, the foremost expert in the adaptive immune system in border tissues, and Gregory Wu, MD PhD, a recent K08 awardee and expert on CNS autoimmunity. The PI will take advantage of his mentorship committee and the vibrant scientific environment of Washington University, one of the world’s premiere medical research institutions, to develop the unexplored topic of the adaptive immune response in the choroid. Uveitis is one of the leading causes of preventable blindness, and while much work has gone in to evaluating the effects of T cell-derived cytokines, there is a significant gap in understanding of the anatomy of the immune response including where the adaptive immune system interfaces with ocular antigens. This deficit has led to toxic and often ineffective systemic therapies as the mainstay of treatment. We show that intraocular antigens are taken up in the choroid, a tissue that has a rich adaptive immune presence. In autoimmune uveitis there is an increase of CD4+ T cells in the choroid, indicating that the choroid plays a vital role as the immune interface between the intraocular space and adaptive immune system. In this proposal, we will test the hypothesis that the adaptive immune system is activated by retinal antigens in the choroid and that this interaction plays a central role in uveitis. We will further elucidate the mechanisms contributing to immune surveillance in the choroid. Understanding the mechanisms behind this process has broad implications in the development of diagnostic testing and targeted therapy that will improve the clinical outcomes in uveitis.

项目摘要： 该项目的总体目标是将主要研究者（PI）开发为独立的临床 - 科学家为眼部自身免疫领域做出了贡献。 PI已获得神经科学博士学位，探索 自适应免疫系统在轴突损伤模型中的作用。他还有其他临床培训 葡萄膜炎和眼部免疫学的眼科和亚科培训，这是其医学的基础 在圣路易斯华盛顿大学眼科与视觉科学系的练习。这 这里概述的五年职业发展计划将利用教学课程的组合 专家合作者的培训和既定研究人员的精通训练以增强他的知识 基础，要学习新的实验模型，他可以在职业生涯中继续使用，并定义研究 他将在他的独立研究计划开始的问题上进行问题。到该计划结束时，他 将获得成为独立调查员所需的技能。 他的主要导师是由R01资助的调查员Rajendra Apte，MD博士学位 培训早期的调查人员，这些调查员已继续从事独立职业。他是杰出的 脉络膜免疫领域的学者，作为临床科学家的背景很强，这对于 帮助PI应对过渡到独立实验室的挑战。 Apte博士将得到支持 雷切尔·卡斯皮（Rachel Caspi）博士，实验性自身免疫性葡萄膜炎的世界领先专家，乔纳森·基普尼斯（Jonathan Kipnis），博士， 边界组织自适应免疫系统的最重要专家，以及Gregory Wu，MD PhD，最近的K08 CNS自身免疫的获奖者和专家。 PI将利用他的指导委员会和 华盛顿大学充满活力的科学环境，这是世界上首次医学研究之一 机构，发展脉络膜中自适应免疫反应的意外主题。 葡萄膜炎是可预防失明的主要原因之一，尽管大量工作已经进行了评估 T细胞衍生的细胞因子的作用，了解免疫的解剖结构存在很大的差距 反应，包括自适应免疫系统与眼部抗原的界面。这种防御已导致 有毒且通常无效的全身疗法是治疗的支柱。我们表明眼内抗原 在脉络膜中被吸收，该组织具有丰富的适应性免疫存在。在自身免疫性葡萄膜炎中 脉络膜中CD4+ T细胞的增加，表明脉络体起着至关重要的作用作为免疫接口 在眼内空间和适应性免疫系统之间。在此提案中，我们将检验以下假设 自适应免疫系统被脉络膜中的视网膜抗原激活，并且这种相互作用在中央 在葡萄膜炎中的作用。我们将进一步阐明有助于脉络膜免疫监视的机制。 了解此过程背后的机制对诊断的发展具有广泛的影响 测试和靶向疗法将改善葡萄膜炎的临床结果。