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:
- 金额:$ 33.65万
- 依托单位:
- 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:
- 关键词:AblationAcquired Immunodeficiency SyndromeAcuteAdrenal Cortex HormonesAffectAnimal ModelAntigensAntiviral AgentsAstrocytesAutoimmune DiseasesAutoimmune ProcessAxonBrainBrain DiseasesBrain scanCD8B1 geneCell DeathCell MaintenanceCellsCentral Nervous System DiseasesCentral Nervous System InfectionsCerebral EdemaCessation of lifeChronicClinicalComplementComplicationDataDemyelinating DiseasesDemyelinationsDiagnosisDiffusion Magnetic Resonance ImagingDiseaseDropoutEquilibriumEvaluationEvolutionFamilyFrequenciesFumaratesFunctional disorderGenesGoalsHematopoieticHighly Active Antiretroviral TherapyHistologicHumanImmuneImmunityImmunologic Deficiency SyndromesImmunologic MonitoringImmunotherapeutic agentIn SituIn VitroIndividualInfectionInfiltrationInflammationInflammatoryInfusion proceduresIntegrin alpha4Integrin alpha4beta1Interferon Type IIInterruptionInterventionJC VirusLifeLinkLoxP-flanked alleleLymphocytic InfiltrateLyticLytic PhaseMagnetic Resonance ImagingMaintenanceMediatingModelingMononuclearMultifocal LesionMultiple SclerosisMusMyelinNeurogliaNonlyticOligodendrogliaPDCD1LG1 genePathogenesisPathway interactionsPatientsPhasePlasma ExchangePlayPolyomavirusPolyomavirus InfectionsPopulationProductionProgressive Multifocal LeukoencephalopathyReactionRelapseRoleSeveritiesSignal TransductionSyndromeT cell differentiationT-LymphocyteTestingTissuesTransgenic MiceTransgenic OrganismsTropismViralVirusVirus DiseasesVirus Replicationcell typedesigndrug withdrawalexhaustionhumanized antibodyin vivoinsightmortalitymouse modelmouse polyomavirusmultiple sclerosis patientmutantnatalizumabneuroinflammationneuropathologynovelpathogenpreventreceptorrecombinasereconstitutionseropositivestemwhite 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Aron Eliot Lukacher其他文献
Aron Eliot Lukacher的其他文献
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{{ truncateString('Aron Eliot Lukacher', 18)}}的其他基金
Deciphering Early Stages of Polyomavirus CNS Pathogenesis and Immunity
破译多瘤病毒中枢神经系统发病机制和免疫的早期阶段
- 批准号:
10449608 - 财政年份:2022
- 资助金额:
$ 33.65万 - 项目类别:
Deciphering Early Stages of Polyomavirus CNS Pathogenesis and Immunity
破译多瘤病毒中枢神经系统发病机制和免疫的早期阶段
- 批准号:
10785321 - 财政年份:2022
- 资助金额:
$ 33.65万 - 项目类别:
Deciphering Early Stages of Polyomavirus CNS Pathogenesis and Immunity
破译多瘤病毒中枢神经系统发病机制和免疫的早期阶段
- 批准号:
10610484 - 财政年份:2022
- 资助金额:
$ 33.65万 - 项目类别:
Defining Early Stages of Polyomavirus CNS Pathogenesis and Immunity
定义多瘤病毒中枢神经系统发病机制和免疫的早期阶段
- 批准号:
10365345 - 财政年份:2016
- 资助金额:
$ 33.65万 - 项目类别:
A Mouse Model to Define Immunovirologic Determinants of Polyomavirus CNS Disease
定义多瘤病毒中枢神经系统疾病免疫病毒学决定因素的小鼠模型
- 批准号:
8853962 - 财政年份:2014
- 资助金额:
$ 33.65万 - 项目类别:
A Mouse Model to Define Immunovirologic Determinants of Polyomavirus CNS Disease
定义多瘤病毒中枢神经系统疾病免疫病毒学决定因素的小鼠模型
- 批准号:
9920216 - 财政年份:2014
- 资助金额:
$ 33.65万 - 项目类别:
A Mouse Model to Define Immunovirologic Determinants of Polyomavirus CNS Disease
定义多瘤病毒中枢神经系统疾病免疫病毒学决定因素的小鼠模型
- 批准号:
9244865 - 财政年份:2014
- 资助金额:
$ 33.65万 - 项目类别:
A Mouse Model to Define Immunovirologic Determinants of Polyomavirus CNS Disease
定义多瘤病毒中枢神经系统疾病免疫病毒学决定因素的小鼠模型
- 批准号:
10133156 - 财政年份:2014
- 资助金额:
$ 33.65万 - 项目类别:
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