Oligodendrocyte extracellular vesicles: a novel therapy for CNS autoimmunity
少突胶质细胞外囊泡:中枢神经系统自身免疫的新疗法
基本信息
- 批准号:10115612
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimal ModelAnimalsAntigen TargetingAntigensAutoantigensAutoimmuneAutoimmune DiseasesAutoimmune ResponsesAutoimmunityCNS autoimmunityCell LineCellsChronicClinicalDataDevelopmentDiseaseEpitope spreadingEpitopesEvolutionExperimental Animal ModelExperimental Autoimmune EncephalomyelitisFailureFlareGeneticGoalsHeterogeneityHumanImmune TargetingImmune ToleranceImmune responseImmune systemImmunityImmunizationImmunosuppressionInjectionsInterferon Type IIInterferonsInterleukin-10IntravenousKnockout MiceKnowledgeMediatingModelingMultiple SclerosisMusMyelinMyelin ProteinsNoseOligodendrogliaOralPathogenesisPathogenicityPatientsPeptidesPeripheralProductionResearchRestRoleRouteSerious Adverse EventSpecificitySystemTestingTherapeuticTherapeutic AgentsTherapeutic EffectTimeTranslationsTreatment EfficacyUncertaintybaseclinically relevantconditional knockoutextracellular vesicleshumanized mouseimmune system functionimmunoregulationin vivomultiple sclerosis patientneuroinflammationnovel therapeuticsparticleperipheral toleranceprogrammed cell death ligand 1prophylacticreconstitutionresponseside effectsuccessvesicular release
项目摘要
SUMMARY: Oligodendrocyte extracellular vesicles: a novel therapy for CNS autoimmunity.
Current therapies for multiple sclerosis (MS) target the immune system in an antigen (Ag)-nonspecific manner,
with potentialy serious side effects due to systemic immunosuppression. A longstanding goal in MS research is
to devise an Ag-specific therapy that would suppress only harmful immune responses, while leaving the rest of
the immune system intact. The prerequisite for Ag-specific therapy is identification of the target Ag. MS
pathogenesis is widely believed to be driven by autoimmunity against myelin Ags. However, the relevant Ag(s)
in MS remains speculative, with the possibility that these Ags differ among patients, and over time in the same
patient. Numerous approaches for Ag-specific suppression of autoimmune neuroinflammation have been proven
in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. These approaches rely on re-
establishing peripheral tolerance for self-Ag by delivering the same self-Ag in a non-inflammatory context (eg. in
PBS) via various routes, such as intravenous (i.v.), oral, or nasal. However, translation of these experimental
strategies into MS therapy has been hampered by uncertainty about the relevant Ags in MS patients. In
addressing this issue, we reasoned that if for tolerance induction we used oligodendrocyte (Ol)-derived
extracellular vesicles (Ol-EVs), which naturally contain most or all of the myelin Ags, it would be unnecessary to
identify the relevant myelin Ag(s) in each patient. Further, we also posited that i.v. injection of Ol-EVs will
suppress EAE, similar to well-documented i.v. tolerance induction by free self-peptide. Indeed, our data show
that Ol-EVs contained all the relevant myelin Ags and upon i.v. injection ameliorated ongoing EAE in an Ag-
dependent manner, suggesting that Ol-EVs can be a universal therapeutic agent for MS. Based on these and
additional preliminary data, we hypothesize that human and mouse Ol-EVs contain all relevant myelin Ags, and
upon i.v. administration will ameliorate EAE induced by various myelin Ags. We additionally hypothesize that this
effect is Ag-dependent and mediated by the IFN-/IL-27/PD-L1 axis. This hypothesis will be tested in the following
specific aims: Aim 1. To determine the therapeutic efficacy of Ol-EVs in several EAE models. Since the
significance of this project is to study Ol-EVs as a potential therapy for MS, and we do not know the relevant
Ag(s) in MS, we will test the hypothesis that OL-EVs/i.v. can suppress EAE induced by any myelin Ag, because
all the relevant Ags are present in OL-EVs. Aim 2. To define the mechanism of EAE suppression by Ol-EVs.
Our preliminary data provide a basis for the hypothesis that Ol-EVs/i.v. induce tolerogenic APCs, which diminish
pathogenic Th cell response and suppress EAE via expression of immunoregulatory molecules. Aim 3. To study
the effects of human Ol-EVs in human myelin Ag-induced EAE, and in humanized mice. We will optimize
production of human Ol-EVs, and test the hypothesis that human Ol-EVs/i.v. have adequate therapeutic efficacy
in EAE models, and in humanized mice to determine if findings in mice are paralleled in this human-like system.
摘要:少突胶质细胞胞外囊泡:一种治疗中枢神经系统自身免疫的新方法。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
A.M. Rostami其他文献
A.M. Rostami的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('A.M. Rostami', 18)}}的其他基金
IL-37: a novel regulator of inflammation in CNS autoimmunity
IL-37:中枢神经系统自身免疫炎症的新型调节剂
- 批准号:
10199564 - 财政年份:2021
- 资助金额:
$ 39万 - 项目类别:
IL-37: a novel regulator of inflammation in CNS autoimmunity
IL-37:中枢神经系统自身免疫炎症的新型调节剂
- 批准号:
10369694 - 财政年份:2021
- 资助金额:
$ 39万 - 项目类别:
Oligodendrocyte extracellular vesicles: a novel therapy for CNS autoimmunity
少突胶质细胞外囊泡:中枢神经系统自身免疫的新疗法
- 批准号:
10361415 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
Mechanisms of GM-CSF effect in CNS autoimmune demyelination
GM-CSF在中枢神经系统自身免疫性脱髓鞘中的作用机制
- 批准号:
10062792 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
The Role of GM-CSF in the Pathogenesis of Multiple Sclerosis
GM-CSF 在多发性硬化症发病机制中的作用
- 批准号:
8767198 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
The Role of GM-CSF in the Pathogenesis of Multiple Sclerosis
GM-CSF 在多发性硬化症发病机制中的作用
- 批准号:
8911388 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
相似海外基金
Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
- 批准号:
495434 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
- 批准号:
10586596 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
- 批准号:
10590479 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
- 批准号:
10642519 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
- 批准号:
23K06011 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
- 批准号:
10682117 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
- 批准号:
10708517 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
- 批准号:
10575566 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
- 批准号:
23K15696 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
- 批准号:
23K15867 - 财政年份:2023
- 资助金额:
$ 39万 - 项目类别:
Grant-in-Aid for Early-Career Scientists