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

基本信息

批准号：
10703729
负责人：
Katayoun Ayasoufi
金额：
$ 24.9万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10703729
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 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 Nervous System Trauma Nervous System control 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 carcinogenesis 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

项目摘要

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.

损害中枢神经系统（CNS）后，免疫系统的抑制是中风，创伤性脑损伤（TBI）和胶质母细胞瘤（GBM）等多样化的神经疾病的常见特征。这种免疫抑制会导致死亡率，并导致免疫调节疗法失败。神经侮辱后的全身免疫抑制的基本机制仍然很大未知。在此提案中，我们专注于胸腺，胸腺是负责儿童和成人T细胞发育的主要免疫器官。我们在各种神经系统损伤后测试了胸腺功能，包括中枢神经系统的病毒感染，肿瘤，无菌炎症，身体损伤和癫痫发作活性。所有侮辱都会导致明显的胸腺反应，在清除受伤后是可逆的。重要的是，外周损伤后没有发生胸腺冲突。使用抛物线症，我们发现胸腺症的不相互作用可以从神经胶质瘤转移到非肿瘤的抛物线，这表明血清衍生的可溶性因子在介导胸腺渗透中的关键作用。具体而言，大于300 kDa的分子量（MW）的血清衍生分子被认为是免疫抑制的。有趣的是，胸腺由中枢神经系统严重支配，但是这种神经在神经系统损伤和免疫抑制中的作用仍然未知。我们首次证明了胸腺由外在神经元（胸腺外的细胞体）和使用狂犬病病毒神经治疗剂的内在神经元（胸腺内的细胞体）严重支配。简而言之，神经侮辱后的多面免疫抑制会改变胸腺，骨髓和脾脏中的免疫稳态。这些免疫器官中这些改变诱导短暂或持久免疫缺陷的范围仍在研究中。胸腺的反应，血清中的免疫抑制因子的存在，骨髓生态位的变化以及长期持久的免疫缺陷在一起，至少部分地说明了神经系统损伤后观察到的免疫缺陷。基于这些数据，我们假设神经系统侮辱会通过可溶性因素和神经损害大脑在系统和局部抑制免疫系统。反过来，这改变了免疫曲目并影响长期免疫力。该假设将在以下三个目的中进行检验：AIM1：确定神经损伤期间血清衍生的免疫抑制因子的分子认同；目标2：确定基线和神经损伤期间胸腺神经的功能；目标3：确定神经损伤后免疫抑制对免疫系统的短暂和持久功能后果。这些目标的成功完成将显着影响对神经损伤期间免疫系统免疫抑制和神经控制的理解，并将帮助我们开发新的治疗剂，以打击大量急性和慢性神经外伤患者的免疫抑制。