Immune response to CNS injury

对中枢神经系统损伤的免疫反应

基本信息

批准号：
9241450
负责人：
Jonathan Kipnis
金额：
$ 34.29万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241450
关键词：
Address Affect Anatomy Antigens Apoptotic Astrocytes Bone Marrow Brain CD4 Positive T Lymphocytes Cells Cerebrospinal Fluid Cessation of life Chimera organism Cues Data Deep Cervical Lymph Node Drainage procedure Event Excision Exhibits Glutamates Goals Growth Factor Immune Immune response Immune system Immunity Impairment Injury Interleukin-13 Interleukin-4 Knockout Mice Lead Light Link Lymphatic Endothelial Cells Lymphatic vessel Lymphocyte Lymphoid Cell Mediating Meningeal Meninges Microglia Modeling Molecular Mus Myeloid Cells Necrosis Nerve Degeneration Neurodegenerative Disorders Neuronal Injury Neurons Nitric Oxide Oligodendroglia Operative Surgical Procedures Pharmacology Phenotype Play Process Production Proteins Recruitment Activity Regulation Research Role Route Secondary to Signal Transduction Sinus Site Spinal cord injury Stimulus T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Time Traumatic CNS injury Vascular Endothelial Growth Factors Vascular blood supply Wallerian Degeneration Work base cell injury cellular targeting central nervous system injury chemokine cytokine deprivation healing in vivo intravital imaging macrophage monocyte neuron loss neuronal survival neuroprotection neurotoxic new therapeutic target novel therapeutics prototype public health relevance receptor response response to injury stem therapeutic target trafficking two-photon

项目摘要

DESCRIPTION (provided by applicant): Traumatic CNS injuries and many neurodegenerative diseases result in the continuous death of neurons. This spread of neuronal death is termed secondary neurodegeneration. Several works over the last two decades have demonstrated the role of the immune system in affecting secondary degeneration. While some subsets of T cells and macrophages are limiting the spread of damage and thus contributing to neuroprotection, others are perpetuating neurodegeneration. Our goal is to better understand what subsets of T cells mediate neuroprotection and what molecular cues recruit these T cells to the site of injury. The ultimate goal is to intervene with this process and boost neuroprotective immunity. We have recently demonstrated a role for both effector and regulatory CD4+ T cells in response to CNS injury. We also showed that neuroprotective T cells, through their production of IL-4, limit the degree of secondary degeneration; however, the precise cellular targets of IL-4-mediated neuroprotection have not been identified to date. Activation of T cells after CNS injury takes place in the CNS-draining deep cervical lymph nodes (dCLNs), and surgical resection of dCLNs results in impaired neuronal survival after CNS injury. Although the connection between cerebrospinal fluid (CSF) and the dCLNs has been appreciated, the exact path of cell trafficking between the two regions was not completely understood. In search for the routes of cell entry and exit to/from the CNS, we serendipitously discovered classical lymphatic vessels in the brain meninges located along the dural sinuses, which carry lymphocytes and myeloid cells and drain CSF and immune cells directly to the dCLNs. Characterization of these vessels may allow us to gain a control over drainage of cellular and soluble CSF constituents and thus possibly alter the immune response to brain antigens. The overarching hypothesis that we aim to address in this proposal is that meningeal lymphatic vessels regulate immune response to CNS injury within the meningeal spaces and the recruited T cells acquire there a Th2 phenotype prior to their entry into the site of injury. Th2 skew and a subsequent IL-4 production mediate neuroprotection at the site of injury. The three specific aims to be addressed in this proposal are: (1) To test th hypothesis that meningeal lymphatic vessels are regulating post-injury meningeal T cell immunity; (2) To test the hypothesis that the combined action of oligodendrocyte-derived IL-33 and ILC2-derived IL-13, skew meningeal T cells to Th2; (3) To define the cellular targets of IL-4-mediated neuroprotection. A successful completion of the aims of this proposal will enhance our understanding of the molecular events that drive a protective immune response after CNS injury and will shed a light on new therapeutic targets for CNS injuries and other neurodegenerative disorders.

描述（由申请人提供）：创伤性中枢神经系统损伤和许多神经退行性疾病导致神经元持续死亡，这种神经元死亡的扩散被称为继发性神经退行性变。过去二十年的几项工作已经证明了免疫系统在影响继发性神经退行性疾病中的作用。虽然 T 细胞和巨噬细胞的某些亚群限制了损伤的扩散，从而有助于神经保护，但其他亚群却使神经变性永久化，我们的目标是更好地了解 T 细胞亚群介导的神经变性。神经保护以及哪些分子信号将这些 T 细胞招募到损伤部位，最终目标是干预这一过程并增强神经保护性免疫。研究表明，神经保护性 T 细胞通过产生 IL-4 来限制继发性变性的程度；然而，迄今为止，中枢神经系统损伤后 T 细胞激活的精确细胞靶点尚未确定。尽管脑脊液 (CSF) 和 dCLN 之间的联系已得到认可，但 dCLN 之间的细胞运输的确切路径仍然存在。在寻找细胞进出中枢神经系统的路线时，我们不完全了解这两个区域，我们偶然发现了位于沿脑膜的经典淋巴管。硬脑膜窦，携带淋巴细胞和骨髓细胞，并将脑脊液和免疫细胞直接排出至 dCLN。这些血管的特征可能使我们能够控制细胞和可溶性脑脊液成分的排出，从而可能改变对脑抗原的免疫反应。我们在本提案中旨在解决的首要假设是，脑膜淋巴管调节脑膜间隙内对中枢神经系统损伤的免疫反应，并且招募的 T 细胞在进入脑膜腔之前获得 Th2 表型。 Th2 偏差和随后的 IL-4 产生介导损伤部位的神经保护。本提案要解决的三个具体目标是：（1）检验脑膜淋巴管调节损伤后脑膜的假设。 (2) 检验少突胶质细胞来源的 IL-33 和 ILC2 来源的 IL-13 的联合作用使脑膜 T 细胞偏向 Th2 的假设； IL-4介导的神经保护的细胞靶点的成功完成该提案的目标将增强我们对中枢神经系统损伤后驱动保护性免疫反应的分子事件的理解，并将揭示中枢神经系统损伤和其他疾病的新治疗靶点。神经退行性疾病。