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.

项目概要： 该项目的总体目标是将主要研究者（PI）培养为独立的临床医生- 对眼部自身免疫领域做出贡献的科学家。PI获得了神经科学博士学位，探索 适应性免疫系统在轴突损伤模型中的作用。他还接受了以下方面的临床培训： 眼科和葡萄膜炎和眼免疫学的亚专业培训，这构成了他的医学基础。 在圣路易斯的华盛顿大学眼科和视觉科学系实习。的 这里概述的五年职业发展计划将利用教学课程的组合，个性化 来自专家合作者的培训，以及来自知名调查人员的指导，以提高他的知识 基地，学习新的实验模型，他可以继续在他的职业生涯中使用，并定义研究 他将以此为基础开始他的独立研究计划。在节目结束时，他 将获得成为独立调查员所需的技能。 他的主要导师是Rajendra Apte，医学博士，R 01资助的研究人员，有纵向跟踪记录 培训早期的调查人员，他们已经开始了富有成效的独立职业生涯。他是一位杰出的 他是脉络膜免疫领域的学者，并具有作为临床科学家的强大背景，这对于 帮助PI应对过渡到独立实验室所涉及的挑战。Apte博士将得到支持 由Rachel Caspi博士，世界领先的实验性自身免疫性葡萄膜炎专家，Jonathan Kipnis博士， 最重要的专家在适应性免疫系统在边界组织，和格雷戈里吴，医学博士，博士，最近的K 08 获奖者和中枢神经系统自身免疫专家。PI将利用他的导师委员会和 华盛顿大学充满活力的科学环境，世界上首屈一指的医学研究之一 机构，发展脉络膜适应性免疫反应的未探索的主题。 葡萄膜炎是可预防性失明的主要原因之一，虽然许多工作已经在评估 T细胞衍生的细胞因子的作用，在理解免疫系统的解剖结构方面存在着重大的差距。 免疫应答包括适应性免疫系统与眼抗原相互作用的地方。这一赤字导致 毒性和通常无效的全身疗法作为治疗的主要手段。我们发现眼内抗原 被脉络膜吸收，脉络膜是一种具有丰富适应性免疫存在的组织。在自身免疫性葡萄膜炎中， 脉络膜中CD 4 + T细胞的增加，表明脉络膜作为免疫界面起着至关重要的作用 眼内空间和适应性免疫系统之间的关系。在本提案中，我们将检验以下假设： 适应性免疫系统被脉络膜中的视网膜抗原激活， 在葡萄膜炎中的作用我们将进一步阐明脉络膜免疫监视的机制。 了解这一过程背后的机制对诊断性疾病的发展具有广泛的意义。 测试和靶向治疗，将改善葡萄膜炎的临床结果。