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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.

摘要