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Pathogenesis of Mouse Polyomavirus-associated CNS Demyelination

小鼠多瘤病毒相关中枢神经系统脱髓鞘的发病机制

基本信息

批准号：
9185385
负责人：
Aron Eliot Lukacher
金额：
$ 33.65万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
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：
2016-05-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9185385
关键词：
Ablation Acquired Immunodeficiency Syndrome Acute Adrenal Cortex Hormones Affect Animal Model Antigens Antiviral Agents Astrocytes Autoimmune Diseases Autoimmune Process Axon Brain Brain Diseases Brain scan CD8B1 gene Cell Death Cell Maintenance Cells Central Nervous System Diseases Central Nervous System Infections Cerebral Edema Cessation of life Chronic Clinical Complement Complication Data Demyelinating Diseases Demyelinations Diagnosis Diffusion Magnetic Resonance Imaging Disease Dropout Equilibrium Evaluation Evolution Family Frequencies Fumarates Functional disorder Genes Goals Hematopoietic Highly Active Antiretroviral Therapy Histologic Human Immune Immunity Immunologic Deficiency Syndromes Immunologic Monitoring Immunotherapeutic agent In Situ In Vitro Individual Infection Infiltration Inflammation Inflammatory Infusion procedures Integrin alpha4 Integrin alpha4beta1 Interferon Type II Interruption Intervention JC Virus Life Link LoxP-flanked allele Lymphocytic Infiltrate Lytic Lytic Phase Magnetic Resonance Imaging Maintenance Mediating Modeling Mononuclear Multifocal Lesion Multiple Sclerosis Mus Myelin Neuroglia Nonlytic Oligodendroglia PDCD1LG1 gene Pathogenesis Pathway interactions Patients Phase Plasma Exchange Play Polyomavirus Polyomavirus Infections Population Production Progressive Multifocal Leukoencephalopathy Reaction Relapse Role Severities Signal Transduction Syndrome T cell differentiation T-Lymphocyte Testing Tissues Transgenic Mice Transgenic Organisms Tropism Viral Virus Virus Diseases Virus Replication cell type design drug withdrawal exhaustion humanized antibody in vivo insight mortality mouse model mouse polyomavirus multiple sclerosis patient mutant natalizumab neuroinflammation neuropathology novel pathogen prevent receptor recombinase reconstitution seropositive stem white matter

项目摘要

ABSTRACT Progressive Multifocal Leukoencephalopathy (PML) is a life-threatening demyelinating brain disease in immune-compromised individuals caused by the JC polyomavirus (JCV), a ubiquitous human-only pathogen. No anti-JCV agents are available. PML is a significant complication for patients receiving long-term natalizumab, a humanized antibody against α4 integrins that dramatically reduces relapses in multiple sclerosis (MS) patients. PML is being diagnosed with increasing frequency in patients treated with other immunomodulatory agents (e.g., Rituxamab, Efalixumab, Fingolimod, and dimethyl fumarate) as well. Drug withdrawal is often complicated by Immune Reconstitution Inflammatory Syndrome (IRIS), a severe inflammatory reaction with paradoxical worsening of demyelination that carries a high mortality rate. Lack of a tractable animal model for PML is a widely recognized hurdle to defining pathogenesis of demyelination in PML and PML-IRIS. Using mouse polyomavirus (MPyV), we developed a robust model of polyomavirus-associated demyelinating leukoencephalitis (brain white matter inflammation), with viral infection and T cell infiltration localized to subcortical white matter. For Specific Aim 1, we hypothesize that MPyV replicates predominantly in astrocytes early in infection, with neuroinflammation rather than viral infection causing oligodendrocyte loss; with α4 integrin blockade, however, oligodendrocyte dropout is delayed and results from MPyV replication extending to oligodendrocytes. To test this hypothesis, we developed a novel floxed MPyV mutant to conditionally restrict viral replication in Cre recombinase-expressing astrocytes or oligodendrocytes, and will use a mouse line with ablation of the α4 integrin gene in hematopoietic cells. Histologic and immunohistologic evaluation of MPyV-infected brains will be complemented by MRI diffusion tensor imaging to detect and quantify multifocal lesions and axon organizational integrity in whole brain scans. For Specific Aim 2 we hypothesize that IFN-γ, produced by MPyV-specific CD8 T cells, mediates a demyelinating leukoencephalitis in early infection, but confers protection in persistent infection. To test this hypothesis, we will use transgenic mice to conditionally ablate IFN-γ signaling in astrocytes and oligodendrocytes, and mice made chimeric with IFN-γ-sufficient/-deficient, MPyV-specific TCR transgenic CD8 T cells. For Specific Aim 3 we hypothesize that the PD-1:PD-L1 pathway balances MPyV-specific CD8 T cell-mediated control of CNS infection against their ability to promote neuroinflammation and demyelination. Anti-MPyV CD8 T cells infiltrating the brain are stably maintained and uniformly upregulate PD-1 inhibitory receptors. To test this hypothesis, we will study the in vivo function and fate of PD-1-/- T cells in brains of MPyV-infected mice, and apply chronic intracerebroventricular infusion of anti-PD-L1. This model of polyomavirus-associated CNS disease may provide insights for strategies to prevent or stem progression of this devastating demyelinating leukoencephalitis associated with immunomodulatory therapies for MS and other autoimmune/inflammatory diseases.

抽象的进行性多灶性白质脑病 (PML) 是一种危及生命的脱髓鞘性脑病由 JC 多瘤病毒 (JCV)（一种普遍存在的人类病原体）引起的免疫受损个体。没有可用的抗 JCV 药物。对于长期接受治疗的患者来说，PML 是一个严重的并发症。那他珠单抗，一种针对 α4 整合素的人源化抗体，可显着减少多发性硬化症的复发（多发性硬化症）患者。在接受其他治疗的患者中，PML 的诊断频率越来越高免疫调节剂（例如利妥昔单抗、依法利昔单抗、芬戈莫德和富马酸二甲酯）。药品戒断通常会因免疫重建炎症综合征（IRIS）而变得复杂，这是一种严重的疾病炎症反应与脱髓鞘的矛盾恶化具有很高的死亡率。缺乏一个易处理的 PML 动物模型是定义 PML 脱髓鞘发病机制的一个广泛公认的障碍和 PML-IRIS。使用小鼠多瘤病毒（MPyV），我们开发了与多瘤病毒相关的稳健模型脱髓鞘性白质脑炎（脑白质炎症），伴有病毒感染和 T 细胞浸润定位于皮层下白质。对于特定目标 1，我们假设 MPyV 主要复制在感染早期的星形胶质细胞中，神经炎症而不是病毒感染导致少突胶质细胞损失；然而，通过α4整合素阻断，少突胶质细胞的脱落被延迟并且是MPyV复制的结果延伸至少突胶质细胞。为了验证这一假设，我们开发了一种新型 floxed MPyV 突变体有条件地限制表达 Cre 重组酶的星形胶质细胞或少突胶质细胞中的病毒复制，并将使用消除造血细胞中 α4 整合素基因的小鼠系。组织学和免疫组织学对 MPyV 感染大脑的评估将辅以 MRI 扩散张量成像来检测和在全脑扫描中量化多灶性病变和轴突组织完整性。对于具体目标 2，我们假设 MPyV 特异性 CD8 T 细胞产生的 IFN-γ 介导脱髓鞘性白质脑炎早期感染，但在持续感染时提供保护。为了验证这个假设，我们将使用转基因小鼠有条件地消除星形胶质细胞和少突胶质细胞中的 IFN-γ 信号传导，并与小鼠嵌合 IFN-γ 充足/缺乏、MPyV 特异性 TCR 转基因 CD8 T 细胞。对于具体目标 3，我们假设 PD-1:PD-L1 通路平衡 MPyV 特异性 CD8 T 细胞介导的 CNS 感染控制促进神经炎症和脱髓鞘的能力。浸润大脑的抗 MPyV CD8 T 细胞稳定维持并一致上调 PD-1 抑制受体。为了验证这个假设，我们将研究体内 MPyV感染小鼠脑内PD-1-/- T细胞的功能和命运，并应用于慢性脑室内输注抗PD-L1。这种多瘤病毒相关中枢神经系统疾病模型可能为策略提供见解预防或阻止这种与以下疾病相关的破坏性脱髓鞘性白质脑炎的进展针对多发性硬化症和其他自身免疫/炎症性疾病的免疫调节疗法。