Nervous system control and regulation of the immune system following neurological insults

神经系统损伤后的神经系统控制和免疫系统调节

• 批准号: 10463740
• 负责人: Katayoun Ayasoufi
• 金额: $ 10.45万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463740
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adult; Affect; Antigens; Atrophic; Biochemical; Bone Marrow; Bone Marrow Transplantation; Brain; Brain Injuries; CD4 Positive T Lymphocytes; Cell Count; Cells; Central Nervous System Neoplasms; Central Nervous System Viral Diseases; Chemicals; Child; Chronic; Clinic; Data; Defect; Denervation; Ensure; Etiology; Failure; Fractionation; Glioblastoma; Glioma; Goals; Health; Homeostasis; Hospitals; Immune; Immune response; Immune system; Immunity; Immunological Models; Immunologics; Immunosuppression; Immunotherapy; Inflammation; Injury; Malignant neoplasm of brain; Malignant neoplasm of central nervous system; Maps; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Molecular Weight; Morbidity - disease rate; Nervous System Trauma; Nervous System control; Nervous system structure; Neuraxis; Neuroimmune; Neurologic; Neurological Models; Neurology; Neurons; Opportunistic Infections; Organ; Parabiosis; Pathway interactions; Patients; Peripheral; Proteins; Publishing; Rabies virus; Research; Role; Seizures; Serum; Spleen; Sterility; Stroke; Systems Development; T cell reconstitution; T memory cell; T-Cell Development; T-Lymphocyte; Testing; Thymus Gland; Time; Traumatic Brain Injury; Viral Encephalitis; Work; anti-tumor immune response; base; central nervous system injury; clinically relevant; cohort; combat; immunomodulatory therapies; immunoregulation; in vitro Assay; mortality; nerve supply; nervous system disorder; neuroimmunology; novel; novel therapeutics; primary lymphoid organ; programs; response; stroke patient; success; supportive environment; thymus transplantation

Suppression of the immune system following damage to the central nervous system (CNS) is a common feature of neurological diseases as diverse as stroke, traumatic brain injury (TBI), and glioblastoma (GBM). This immunosuppression causes mortality and leads to the failure of immune-modulating therapies. The underlying mechanisms of systemic immunosuppression following neurological insults remain largely unknown. In this proposal, we focus on the thymus, the primary immune organ responsible for T cell development in children and adults. We tested thymic function following various neurological insults, including viral infections of the CNS, tumors, sterile inflammation, physical injury, and seizure activity. All insults resulted in significant thymic involution that was reversible upon clearance of the injury. Importantly, thymic involution did not occur following peripheral insults. Using parabiosis, we found that thymic involution was transferable from glioma- bearing to non-tumor-bearing parabionts demonstrating the crucial role of serum-derived soluble factors in mediating thymic involution. Specifically, serum-derived molecules with molecular weights (MW) larger than 300 kDa were deemed immunosuppressive. Interestingly, the thymus is heavily innervated by the CNS, yet the role of this innervation during neurological injuries and immunosuppression remains unknown. We demonstrated, for the first time, that the thymus is heavily innervated by both extrinsic neurons (cell bodies outside of the thymus), and intrinsic neurons (cell bodies within the thymus) using rabies virus neurotracers. In short, the multifaceted immunosuppression following neurological insults alters immune homeostasis in the thymus, bone marrow, and the spleen. The extents to which these alterations in the immune organs induce transient or long-lasting immunological defects remain understudied. Thymic involution, presence of immunosuppressive factors in serum, changes within the bone marrow niche, and long-lasting immunological defects together account, at least in part, for immune deficiencies observed following neurologic injuries. Based on these data, we hypothesized that following neurological insults the brain suppresses the immune system both systemically and locally through soluble factors and innervation. This in turn alters the immune repertoire and affects long-term immunity. This hypothesis will be tested in the following three aims: Aim1: To determine the molecular identity of serum-derived immunosuppressive factors during neurological insults; Aim 2: To determine the function of thymic innervation at baseline and during neurological insults; Aim 3: To determine transient and long-lasting functional consequences of immunosuppression on the immune system following neurological injuries. Successful completion of these aims will significantly impact understanding of immunosuppression and nervous control of the immune system during neurological injuries and will help us develop new therapeutics to combat immunosuppression in a large cohort of patients with acute and chronic neurological traumas.

中枢神经系统 (CNS) 受损后免疫系统受到抑制是中风、创伤性脑损伤 (TBI) 和胶质母细胞瘤 (GBM) 等多种神经系统疾病的共同特征。这种免疫抑制会导致死亡并导致免疫调节疗法的失败。神经损伤后全身免疫抑制的潜在机制仍然很大程度上未知。在这项提案中，我们重点关注胸腺，它是负责儿童和成人 T 细胞发育的主要免疫器官。我们测试了各种神经损伤后的胸腺功能，包括中枢神经系统病毒感染、肿瘤、无菌炎症、身体损伤和癫痫发作。所有损伤都会导致显着的胸腺复旧，这种复旧在损伤清除后是可逆的。重要的是，外周损伤后胸腺复旧并未发生。利用联体共生，我们发现胸腺复旧可以从胶质瘤转移到非肿瘤联体生物，这证明了血清来源的可溶性因子在介导胸腺复旧中的关键作用。具体来说，分子量 (MW) 大于 300 kDa 的血清衍生分子被认为具有免疫抑制作用。有趣的是，胸腺受到中枢神经系统的严重支配，但这种神经支配在神经损伤和免疫抑制期间的作用仍然未知。我们使用狂犬病病毒神经示踪剂首次证明胸腺受到外在神经元（胸腺外的细胞体）和内在神经元（胸腺内的细胞体）的严重支配。简而言之，神经损伤后的多方面免疫抑制改变了胸腺、骨髓和脾脏的免疫稳态。免疫器官的这些改变在多大程度上引起短暂或长期的免疫缺陷仍有待研究。胸腺退化、血清中免疫抑制因子的存在、骨髓生态位内的变化以及长期持续的免疫缺陷共同至少部分地解释了神经损伤后观察到的免疫缺陷。基于这些数据，我们假设，在神经损伤后，大脑通过可溶性因子和神经支配系统性和局部性地抑制免疫系统。这反过来会改变免疫系统并影响长期免疫力。该假设将在以下三个目标中得到检验： 目标1：确定神经损伤期间血清源性免疫抑制因子的分子特性；目标 2：确定基线时和神经损伤期间胸腺神经支配的功能；目标 3：确定神经损伤后免疫抑制对免疫系统的短暂和长期功能影响。成功完成这些目标将极大地影响对神经损伤期间免疫抑制和免疫系统神经控制的理解，并将帮助我们开发新的疗法来对抗大量急性和慢性神经创伤患者的免疫抑制。