Immunoregulation of Herpes Encephalitis By Microglia

小胶质细胞对疱疹性脑炎的免疫调节

基本信息

批准号：
7174616
负责人：
James R Lokensgard
金额：
$ 24.81万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-01 至 2008-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7174616
关键词：
Acyclovir Address Adoptive Transfer Antibodies Benzodiazepine Receptor Benzodiazepines Biological Response Modifiers Brain Brain Injuries Brain region CCL2 gene CD8-Positive T-Lymphocytes Cells Central Nervous System Infections Central Nervous System Viral Diseases Defense Mechanisms Development Down-Regulation Encephalitis Goals Herpes encephalitis Herpesvirus 1 Human Immune Immune response Immune system Immunocompromised Host In Situ In Vitro Inbred BALB C Mice Infection Infiltration Injury Investigation Knowledge Laboratory Research Leukocyte Trafficking Leukocytes Ligands Lymphocyte Macrophage Inflammatory Proteins Mediating Microglia Modeling Monocyte Chemoattractant Proteins Mus Nature Neuraxis Neurons Neuropathogenesis Nude Mice Numbers Pathogenesis Pathology Patients Peripheral Phenotype Play Production Proteins Research Project Grants Resistance Role Series Slice Somatic Cell T-Cell Depletion T-Lymphocyte Testing Therapeutic Viral Virus Virus Diseases chemokine cytokine design immunoregulation in vivo insight loss of function neuroinflammation neuropathology neurotoxic neurotoxicity neutralizing antibody novel therapeutics pathogen research study response trafficking

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus 1 (HSV) is an important opportunistic pathogen in HIV-1-infected patients as well as the cause of a devastating CNS infection in normal hosts. Although immune responses to HSV have been the subject of intense investigation, the role of immune-mediated pathology in HSV-related brain damage is unknown. In this proposal, the central hypothesis to be tested is that chemokines produced by microglial cells in response to HSV infection initiate a cascade of neuroimmune responses that result in the serious brain damage seen during herpes encephalitis. To test this hypothesis, chemokine production in the brains of HSV-infected mice will be compared to that in cultures of highly purified murine glial and neuronal cells, and in murine organotypic brain slices infected with HSV. This approach will allow us to differentiate microglial cell chemokine production from that of cells of the somatic immune system. Additionally, the use of organotypic brain slice cultures will enable us to specifically deplete microglial cells for "loss-of-function" experiments. We will then investigate the neurotoxic effects of microglial cell-produced immune mediators on cultured murine neurons. Microglia-driven leukocyte trafficking into the brain will be investigated by determining if neutralizing antibodies to chemokines inhibit T-cell infiltration. The neuropathogenic role of T-cell infiltration will be studied by determining if depletion of T-cells in vivo will delay encephalitis and whether adoptive transfer of HSV-specific lymphocytes restores the encephalitis phenotype. Comparing neuropathology in brain slice cultures with and without the transfer of HSV-specific CD4 + and CD8 +lymphocytes, will allow us to distinguish between injury generated by viral infection and brain damage provoked by immunopathogenic mechanisms. Downregulation of microglial cell chemokine production through peripheral benzodiazepine (BDZ) receptor-mediated cellular deactivation will then be examined. We will determine if deactivation of microglia with BDZs suppresses the production of neurotoxic factors. Finally, we will study the effects of BDZ ligands on chemokine production, T-cell trafficking, and the development of encephalitis in vivo. These in vivo, in vitro, and ex vivo models will provide us with the ability to investigate neuropathogenesis, neuroinflammation, neurotoxicity, and neuroimmune-mediated pathology occurring during herpes encephalitis. Knowledge gained from these studies will increase our understanding of the role of microglial cells and chemokine networks that regulate brain inflammation during herpes encephalitis with the ultimate goal of finding new therapy for this serious brain infection.

描述（由申请人提供）：单纯疱疹病毒 1 (HSV) 是 HIV-1 感染患者的重要机会病原体，也是正常宿主中毁灭性中枢神经系统感染的原因。尽管针对 HSV 的免疫反应一直是深入研究的主题，但免疫介导的病理学在 HSV 相关脑损伤中的作用尚不清楚。在该提案中，要测试的中心假设是，小胶质细胞响应 HSV 感染而产生的趋化因子引发了一系列神经免疫反应，导致疱疹脑炎期间出现的严重脑损伤。为了检验这一假设，将HSV感染小鼠大脑中趋化因子的产生与高度纯化的小鼠神经胶质细胞和神经元细胞培养物以及感染HSV的小鼠器官型脑切片中的趋化因子产生进行比较。这种方法将使我们能够区分小胶质细胞趋化因子的产生与体细胞免疫系统细胞的趋化因子产生。此外，使用器官型脑切片培养物将使我们能够专门消耗小胶质细胞以进行“功能丧失”实验。然后我们将研究小胶质细胞产生的免疫介质对培养的小鼠神经元的神经毒性作用。将通过确定趋化因子的中和抗体是否抑制 T 细胞浸润来研究小胶质细胞驱动的白细胞流入大脑。将通过确定体内 T 细胞的消耗是否会延迟脑炎以及 HSV 特异性淋巴细胞的过继转移是否恢复脑炎表型来研究 T 细胞浸润的神经病理作用。比较有和没有 HSV 特异性 CD4 + 和 CD8 + 淋巴细胞转移的脑切片培养物中的神经病理学，将使我们能够区分病毒感染引起的损伤和免疫致病机制引起的脑损伤。然后将检查通过外周苯二氮卓（BDZ）受体介导的细胞失活对小胶质细胞趋化因子产生的下调。我们将确定用 BDZ 使小胶质细胞失活是否会抑制神经毒性因子的产生。最后，我们将研究 BDZ 配体对趋化因子产生、T 细胞运输和体内脑炎发展的影响。这些体内、体外和离体模型将为我们提供研究疱疹脑炎期间发生的神经发病机制、神经炎症、神经毒性和神经免疫介导的病理学的能力。从这些研究中获得的知识将增加我们对小胶质细胞和趋化因子网络在疱疹脑炎期间调节脑部炎症的作用的理解，最终目标是找到治疗这种严重脑部感染的新疗法。