Role of CD8 T cell-mediated Pathology in Globoid Cell Leukodystrophy
CD8 T 细胞介导的病理学在球状细胞脑白质营养不良中的作用
基本信息
- 批准号:10634808
- 负责人:
- 金额:$ 51.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:5 year oldAddressAffectAntibodiesAntigen-Presenting CellsAntigensAutomobile DrivingBehavioralBiochemicalBloodBody Weight decreasedBrainCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCell TherapyCellsCellular ImmunityCentral Nervous SystemCentral Nervous System DiseasesCessation of lifeChildClinicalCognitive deficitsComplexCytometryCytotoxic T-LymphocytesDataDemyelinationsDevelopmentDiseaseEffectivenessFlow CytometryFutureGenesGeneticGenetic DiseasesGloboid cell leukodystrophyHistologicHumanImageImmuneImmunityInflammationInflammatoryInvestigational TherapiesKnockout MiceKnowledgeLesionLife ExpectancyLipidsLive BirthLocationLongevityMapsMediatingMeningealModelingMolecularMotorMusMutationNatureNerve DegenerationNerve TissueNonsense CodonOligodendrogliaOnset of illnessOutcomeOutcome MeasureOutcome StudyParalysedPathogenesisPathogenicityPathologicPathologyPhenotypePlayPopulationProcessPsychosineReporter GenesRoleT cell clonalityT-Cell DepletionT-LymphocyteTechnologyTestingTherapeuticTherapeutic InterventionTimeTissuesTransgenic AnimalsTransgenic Organismsadaptive immunitybrain tissuecell typecentral nervous system demyelinating disordercytokinecytotoxic CD8 T cellscytotoxicitydefined contributiondisabilitygalactosylceramidasegene therapygenetic approachgenetic profilingimprovedinsightloss of functionloss of function mutationmouse modelmultidisciplinaryneuroinflammationneuropathologynovelpharmacologicpostnatalpreservationpreventresponsesingle-cell RNA sequencingspatial relationshipsuccesstooltranscriptome sequencingtranscriptomicswhite matter
项目摘要
Abstract
Globoid cell leukodystrophy (GLD) or Krabbe's disease is a fatal genetic demyelinating disease of the central
nervous system affecting 1 in 100,000 live births with no cure or effective long-term treatment. GLD is caused
by loss-of-function mutations in the galactosylceramidase (galc) gene, where loss of GALC enzymatic function
results in toxic accumulation of its substrate, a lipid called galactosylsphingosine or `psychosine'. Psychosine
cytotoxicity is considered the basis of several key pathologies in GLD. Neuropathology in GLD is marked by
profound demyelination and inflammation. However, molecular details of these processes are limited, leaving
few therapeutic options. Early histological evidence for CD8+ T cells within demyelinated lesions in both the twi
mouse brain and human GLD brain had suggested a role for adaptive immunity in this disease. However, the
function of CD8+ T cells in GLD has not been previously determined. To address this gap in our knowledge, we
analyzed the timing of T cell population changes by flow cytometry in CNS tissues from the twitcher mouse
model of GLD and compared with wt littermates. We identified a rapid and protracted elevation of T cells in the
twi CNS that was coincident with the onset of clinical disease at postnatal day 21 (P21). These data were
confirmed using single-cell RNA sequencing on twi and wt littermate brain tissues from which identified a 9-fold
increase in CD8+ T cells in twi mouse brains at P21. Our transcriptomic data also defined the CD8+ population
as cytotoxic T lymphocytes (CTLs). To test the function of CD8+ CTLs in GLD-like disease in twi mice, we
depleted CD8+ T cells by administering anti-CD8 antibody to twi mice and found that this treatment effectively
prevented disease onset, preserved wellness and completely prevented CNS demyelination while also
attenuating pro-inflammatory cytokine levels in brain and blood. These novel and highly translational data
portend a pathogenic role for CD8+ T cells in GLD and underlie the basis for our overall hypothesis that CD8+
T cells are pathogenic in GLD and directly contribute to disease. Accordingly, Aim 1 will characterize the
spatial and temporal development of CD8+ T cells in twi mice and challenge the contribution of CD8+ T cells
using knockout mouse lines to then assess clinical, biochemical, and pathological outcomes. Aim 2 will define
the overall nature of adaptive immunity by evaluating contribution of CD4+ T cells to CD8+ T cell-mediated
immunity in twi mice using targeted depletion and genetic strategies. Aim 3 will identify and profile the timing,
and location T cells responding to authentic antigen, the clonality of the T cells using T cell β chain VDJ
phenotyping, and then identify the nature of the antigen presenting cell types using transgenic reporter mice.
These multi-disciplinary studies will interrogate a previously unrecognized CD8+ T cell neuroinflammatory
response in GLD. Outcomes of these studies are expected to fill an important gap in our understanding on the
fundamental cellular pathological mechanisms underlying the development CD8+ T cell mediated
neuropathology and disease in GLD.
摘要
球样细胞白质营养不良症(GLD)或Krabbe病是一种致命的遗传性脱髓鞘疾病,位于
神经系统影响每100,000名活产儿中就有1名,没有治愈或有效的长期治疗。GLD是由
由于半乳糖基神经酰胺酶(GalC)基因功能丧失突变,其中GALC酶功能丧失
导致其底物的有毒堆积,一种称为半乳糖基鞘氨醇或“神经氨酸”的脂类。精神病患者
细胞毒性被认为是GLD几个关键病理机制的基础。GLD的神经病理学表现为
严重的脱髓鞘和炎症。然而,这些过程的分子细节是有限的,留下了
几乎没有治疗选择。双侧脱髓鞘病变中CD8+T细胞的早期组织学证据
小鼠的大脑和人类的GLD大脑表明获得性免疫在这种疾病中起到了作用。然而,
CD8+T细胞在GLD中的功能尚未确定。为了解决我们知识中的这一差距,我们
用流式细胞术分析抽动小鼠中枢神经系统组织中T细胞群变化的时间
GLD模型,并与wt窝产仔进行比较。我们发现T细胞快速而持久地升高。
与出生后第21天的临床发病相符合(P21)。这些数据是
用单细胞rna测序证实从两个和两个小鼠的脑组织中鉴定出9倍的
P21时小鼠脑内CD8+T细胞增多。我们的转录数据也定义了CD8+人群
作为细胞毒性T淋巴细胞(CTL)。为了测试CD8+CTL在两只小鼠的GLD样病中的功能,我们
通过给TWI小鼠注射抗CD8抗体来耗尽CD8+T细胞,并发现这种治疗有效
预防疾病发作,保持健康,完全防止中枢神经系统脱髓鞘,同时还
降低脑部和血液中的促炎细胞因子水平。这些新奇且高度翻译的数据
预示着CD8+T细胞在GLD中的致病作用,并奠定了我们总体假设CD8+的基础
T细胞在GLD中是致病的,并直接导致疾病。因此,目标1将描述
TWI小鼠CD8+T细胞的时空发育及对CD8+T细胞贡献的挑战
使用基因敲除小鼠品系评估临床、生化和病理结果。目标2将定义
通过评估CD4+T细胞对CD8+T细胞介导的贡献来评估获得性免疫的总体性质
靶向耗竭和遗传策略在TWI小鼠中的免疫。目标3将识别和描述时间,
并利用T细胞β链VDJ定位T细胞对正品抗原的反应性、克隆性
表型,然后用转基因报告鼠鉴定抗原提呈细胞类型的性质。
这些多学科研究将询问一种以前未被识别的CD8+T细胞神经炎性
以GLD表示的响应。这些研究的结果有望填补我们对
CD8+T细胞介导发育的基本细胞病理机制
GLD的神经病理与疾病。
项目成果
期刊论文数量(0)
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Stephen J Crocker其他文献
Stephen J Crocker的其他文献
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{{ truncateString('Stephen J Crocker', 18)}}的其他基金
The Contribution of Central Nervous System Demyelination to Bladder Dysfuntion
中枢神经系统脱髓鞘对膀胱功能障碍的影响
- 批准号:
10352892 - 财政年份:2021
- 资助金额:
$ 51.91万 - 项目类别:
Proteomic and Functional Analyses of Astrocyte Exosomes
星形胶质细胞外泌体的蛋白质组学和功能分析
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8893411 - 财政年份:2015
- 资助金额:
$ 51.91万 - 项目类别:
Development of a conditional T1MP-1 knockout mouse
条件性T1MP-1基因敲除小鼠的研制
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8417649 - 财政年份:2012
- 资助金额:
$ 51.91万 - 项目类别:
Development of a conditional T1MP-1 knockout mouse
条件性T1MP-1基因敲除小鼠的研制
- 批准号:
8283645 - 财政年份:2012
- 资助金额:
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