Detection of disease-relevant CD8+ T cells in Multiple Sclerosis

多发性硬化症中疾病相关 CD8 T 细胞的检测

• 批准号: 10641813
• 负责人: Joseph John Sabatino
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10641813
• 关键词: Adaptive Immune System; Advanced Technology Center; Affect; Alleles; Animal Model; Antigens; B cell therapy; B-Lymphocytes; Blood; Blood Cells; Blood Vessels; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Separation; Cell surface; Cells; Central Nervous System; Cerebrospinal Fluid; Clinical; Clonal Expansion; Data; Demyelinating Diseases; Demyelinations; Detection; Disease; Environment; Epitopes; Equipment; Faculty; Frequencies; Funding; Future; Goals; HLA-A gene; HLA-A2 Antigen; HLA-A3 Antigen; HLA-DRB1; Human; Immune; Immune system; Immunology; Infiltration; Inflammatory; Injury; Institution; K-Series Research Career Programs; Lead; Mediating; Mediator; Memory; Mentors; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Neurologic; Neurology; Neurosciences; Pathogenesis; Pathogenicity; Patients; Peptide/MHC Complex; Persons; Phenotype; Population; Positioning Attribute; Predisposition; Probability; Process; Production; Regulation; Research; Research Personnel; Research Proposals; Role; Scientist; Specificity; Spinal Cord; Stains; T cell receptor repertoire sequencing; T-Lymphocyte; T-Lymphocyte Epitopes; T-cell receptor repertoire; Testing; Training; Transgenic Mice; Tumor Immunity; Viral; Work; career; comparison control; cytokine; cytotoxic; exhaustion; experience; improved; insight; multiple sclerosis patient; nervous system disorder; next generation sequencing; novel; novel therapeutic intervention; peripheral blood; professor; research facility; success; young adult

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is an inflammatory demyelinating neurologic disorder thought to be caused by immune-mediated injury against the central nervous system (CNS). The adaptive immune system, in particular, is considered to be a central mediator of MS immunopathogenesis. B cells and CD4+ T cells have historically received greater focus in MS research. CD8+ T cells are best known for their cytotoxic function in viral and tumor immunity, yet compelling evidence suggests an important, but still largely unknown role in MS. I am seeking a K08 Mentored Clinical Scientist Research Career Development Award in order to gain the experience and expertise needed to advance our understanding of T cells in MS. The goal of this K08 application is to delineate which CD8+ T cells are likely important in MS. Two parallel, complementary aims are proposed to achieve this goal. In Specific Aim 1, novel myelin CD8+ T cell epitopes will be identified and characterized in order to test the hypothesis that myelin-reactive CD8+ T cells are more abundant and pro- inflammatory in MS patients compared to control subjects. In Specific Aim 2, CD8+ T cells isolated from the blood and cerebrospinal fluid (CSF) will undergo high throughput next generation sequencing. This aim will test the hypothesis that the CD8+ T cell repertoire in MS patients is less diverse compared to control subjects and CD4+ T cells owing to intrathecal CD8+ T cell clonal expansion. The two aims will be bridged by sequencing the TCR repertoire of myelin-reactive CD8+ T cells from the blood in order to search for myelin-specific clonotypes in the CSF of MS patients. Elucidation of which CD8+ T cell populations are relevant to MS will pave the way toward determining their role in the disease. My long-term goal is to significantly advance our understanding of MS pathogenesis and hopefully provide guidance for novel therapeutic strategies. As I transition to Assistant Professor, I have assembled an outstanding team of mentors and advisors to guide me towards becoming an independent investigator. The research environment at UCSF is unparalleled and offers access to world-class faculty and researchers in the fields of Neurology and Immunology as well as cutting-edge equipment and research facilities, including at the Sandler Neurosciences Building and Center for Advanced Technology where my work will be completed. With the support of my mentors, institution, and the K08 Career Development Award, I am confident I will be well positioned to transition to an independent research career with R01 or equivalent funding by the end of my five-year training plan.

项目总结/摘要 多发性硬化症（MS）是一种炎症性脱髓鞘神经系统疾病，被认为是由 免疫介导的中枢神经系统（CNS）损伤。特别是适应性免疫系统， 被认为是MS免疫发病机制的中心介质。B细胞和CD 4 + T细胞在历史上 在MS研究中得到了更大的关注。CD 8 + T细胞因其在病毒和肿瘤中的细胞毒性功能而闻名 免疫，但令人信服的证据表明，一个重要的，但在很大程度上仍然未知的作用，在MS。 我正在寻求K 08指导临床科学家研究职业发展奖，以获得 经验和专业知识，以促进我们对MS中T细胞的理解。 应用是划定哪些CD 8 + T细胞可能是重要的MS。两个平行的，互补的目标是 建议实现这一目标。在特异性目标1中，将鉴定新的髓磷脂CD 8 + T细胞表位， 为了检验髓磷脂反应性CD 8 + T细胞更丰富和更亲的假设， 与对照受试者相比，MS患者的炎症。在特异性目标2中，从小鼠中分离的CD 8 + T细胞被称为CD 8 + T细胞。 血液和脑脊液（CSF）将经历高通量的下一代测序。这一目标将检验 假设MS患者中的CD 8 + T细胞库与对照受试者相比多样性较低， 由于鞘内CD 8 + T细胞克隆扩增，CD 4 + T细胞减少。这两个目标将通过以下方式实现： 来自血液的髓鞘反应性CD 8 + T细胞的TCR库，以寻找髓鞘特异性克隆型 在MS患者的CSF中。阐明哪些CD 8 + T细胞群与MS相关将铺平道路 以确定它们在疾病中的作用。我的长期目标是大大提高我们对 MS的发病机制，并希望为新的治疗策略提供指导。 当我过渡到助理教授，我已经组建了一个优秀的导师和顾问团队， 引导我成为一名独立调查员UCSF的研究环境是无与伦比的 并提供神经学和免疫学领域世界一流的教师和研究人员以及 尖端设备和研究设施，包括桑德勒神经科学大楼和中心， 先进的技术，我的工作将在那里完成。在我的导师、机构和 K 08职业发展奖，我相信我将很好地过渡到一个独立的研究 在我的五年培训计划结束时，我将获得R 01或同等资金的职业生涯。

项目成果

T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity.

• DOI: 10.1073/pnas.2306572120
• 发表时间: 2023-07-25
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Sagan, Sharon A.;Moinfar, Zahra;Moseley, Carson E.;Dandekar, Ravi;Spencer, Collin M.;Verkman, Alan S.;Ottersen, Ole Petter;Sobel, Raymond A.;Sidney, John;Sette, Alessandro;Anderson, Mark S.;Steinman, Lawrence;Wilson, Michael R.;Sabatino, Joseph J., Jr.;Zamvil, Scott S.
• 通讯作者: Zamvil, Scott S.