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
基本信息
- 批准号:10062792
- 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:2016
- 资助国家:美国
- 起止时间:2016-12-15 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAnimal ModelAntigen-Presenting CellsAutoimmuneAutoimmune DiseasesB-LymphocytesCD4 Positive T LymphocytesCNS autoimmunityCellsChronicChronic PhaseColony-Stimulating Factor ReceptorsDataDemyelinationsDendritic CellsDevelopmentDiseaseExperimental Autoimmune EncephalomyelitisFOXP3 geneGranulocyte-Macrophage Colony-Stimulating FactorGranulocyte-Macrophage Colony-Stimulating Factor ReceptorsHematopoieticHumanIn VitroInflammatoryInterleukin-10KnowledgeLymphoid CellMediator of activation proteinMicrogliaMultiple SclerosisMusNerve RegenerationPathogenesisPathogenicityPeripheralPhenotypePlayProductionRegulatory T-LymphocyteRoleSignal TransductionSystemT-LymphocyteTestingTh1 CellsTherapeutic EffectTimeTissuesTransforming Growth Factor betabasecellular targetingcytokinehuman modelimmunoregulationin vivointerleukin-23macrophagemonocytemonocyte colony stimulating factormultiple sclerosis patientnovelnovel therapeutics
项目摘要
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory
cytokine essential for the development and progression of experimental autoimmune
encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Although GM-CSF is
mainly produced by pathogenic Th17 and Th1 cells, GM-CSF receptor (GM-CSFR) is not
expressed on T and B cells, but is expressed on antigen-presenting cells (APCs). Among them,
Ly6ChiCCR2+ monocytes are essential for the pathogenic role of GM-CSF in EAE. Further, GM-
CSF signaling in peripheral, but not CNS cells, plays a vital role in the development of acute
EAE. However, whether lack of GM-CSF signaling results in development of immunoregulatory
APCs has not been studied, and the role of GM-CSF signaling in CNS cells in EAE chronicity,
for which microglia activation plays a major role, remains unknown.
Our preliminary results for the first time show enhanced production of immunoregulatory
molecules in APCs, and increased IL-10 and Foxp3 expression in CD4+ T cells of mice lacking
GM-CSF. Similarly, neutralizing GM-CSF in human monocyte culture results in an increase of
IL-27 and TGF-β production. Based on these observations, we hypothesize that GM-CSF
induces proinflammatory monocytes, whereas its blockade results in the induction of
immunoregulatory APCs and suppression of EAE. We will test this hypothesis in the following
specific aims: 1) To determine the impact of GM-CSF on phenotype of APCs and T cells in
EAE. We will test the hypothesis that blockade of GM-CSF signaling in monocytes leads to the
development of immunoregulatory APCs that promote development of Tr1/Treg cells, resulting
in suppression of EAE. 2) To investigate the effect of GM-CSF on the phenotype of
microglia/macrophages in chronic phase of EAE. We will test our hypothesis that GM-CSF
promotes activation and pro-inflammatory M1 phenotype of macrophages/microglia in chronic
phase of EAE, which contributes to disease chronicity. 3) To determine the effects of blocking
GM-CSF on phenotype and function of human monocytes. We will test the hypothesis that
GM-CSF promotes development of a proinflammatory phenotype of human monocytes. These
studies should fill the gap in our knowledge on mechanisms of proinflammatory action of GM-
CSF and its relevant cellular targets in EAE/MS, with potential therapeutic effect in certain
autoimmune diseases.
粒细胞巨噬细胞刺激因子(GM-CSF)是一种促炎性
细胞因子对于实验自身免疫的发展和进展至关重要
脑脊髓炎(EAE),一种多发性硬化症的动物模型(MS)。虽然GM-CSF是
GM-CSF受体(GM-CSFR)主要由致病性Th17和Th1细胞产生,不是
在T和B细胞上表达,但在抗原呈递细胞(APC)上表示。他们之中,
LY6CHICCR2+单核细胞对于GM-CSF在EAE中的致病作用至关重要。此外,GM-
外围的CSF信号传导,而不是CNS细胞,在急性发展中起着至关重要的作用
伊。但是,缺乏GM-CSF信号传导是否导致免疫调节的发展
APC尚未研究,GM-CSF信号在CNS细胞中的作用在EAE慢性中,
小胶质细胞活化起主要作用,仍然未知。
我们第一次的初步结果显示免疫调节的产生增强
APC中的分子,以及缺乏小鼠CD4+ T细胞中IL-10和FOXP3表达增加
GM-CSF。同样,在人单核细胞培养中中和GM-CSF导致增加
IL-27和TGF-β产生。基于这些观察结果,我们假设GM-CSF
诱导促炎单核细胞,而其封锁导致诱导
免疫调节APC和EAE的抑制。我们将在以下来检验这一假设
具体目的:1)确定GM-CSF对APC和T细胞表型的影响
伊。我们将检验以下假设:单核细胞中GM-CSF信号的阻断导致
开发促进TR1/Treg细胞发展的免疫调节APC,导致
在镇压EAE中。 2)研究GM-CSF对表型的影响
EAE慢性期的小胶质细胞/巨噬细胞。我们将测试GM-CSF的假设
促进慢性巨噬细胞/小胶质细胞的激活和促炎的M1表型
EAE的阶段,导致疾病慢性。 3)确定阻塞的影响
GM-CSF关于人类单核细胞的表型和功能。我们将检验以下假设
GM-CSF促进了人类单核细胞的促炎表型的发展。这些
研究应填补我们对GM-促炎作用机制的了解的空白。
CSF及其在EAE/MS中的相关细胞靶标具有某些潜在的治疗作用
自身免疫性疾病。
项目成果
期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production.
IL-9 通过抑制 GM-CSF 产生来控制中枢神经系统自身免疫。
- DOI:10.4049/jimmunol.1801113
- 发表时间:2020
- 期刊:
- 影响因子:0
- 作者:Yoshimura,Satoshi;Thome,Rodolfo;Konno,Shingo;Mari,ElisabethR;Rasouli,Javad;Hwang,Daniel;Boehm,Alexandra;Li,Yanhua;Zhang,Guang-Xian;Ciric,Bogoljub;Rostami,Abdolmohamad
- 通讯作者:Rostami,Abdolmohamad
Oligodendrocyte-derived extracellular vesicles as antigen-specific therapy for autoimmune neuroinflammation in mice.
- DOI:10.1126/scitranslmed.aba0599
- 发表时间:2020-11-04
- 期刊:
- 影响因子:17.1
- 作者:Casella G;Rasouli J;Boehm A;Zhang W;Xiao D;Ishikawa LLW;Thome R;Li X;Hwang D;Porazzi P;Molugu S;Tang HY;Zhang GX;Ciric B;Rostami A
- 通讯作者:Rostami A
Chloroquine-treated dendritic cells require STAT1 signaling for their tolerogenic activity.
- DOI:10.1002/eji.201747362
- 发表时间:2018-07
- 期刊:
- 影响因子:5.4
- 作者:Thome R;Bonfanti AP;Rasouli J;Mari ER;Zhang GX;Rostami A;Verinaud L
- 通讯作者:Verinaud L
A serine protease inhibitor induces type 1 regulatory T cells through IFN-γ/STAT1 signaling.
- DOI:10.1038/s41423-019-0354-6
- 发表时间:2020-09
- 期刊:
- 影响因子:24.1
- 作者:Safavi F;Thome R;Li Z;Wang L;Rasouli J;Ciric B;Zhang GX;Rostami A
- 通讯作者:Rostami A
Induction of Peripheral Tolerance in Ongoing Autoimmune Inflammation Requires Interleukin 27 Signaling in Dendritic Cells.
- DOI:10.3389/fimmu.2017.01392
- 发表时间:2017
- 期刊:
- 影响因子:7.3
- 作者:Thomé R;Moore JN;Mari ER;Rasouli J;Hwang D;Yoshimura S;Ciric B;Zhang GX;Rostami AM
- 通讯作者:Rostami AM
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A.M. Rostami其他文献
A.M. Rostami的其他文献
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{{ 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:
10115612 - 财政年份:2020
- 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:
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:
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