Analysis of vascular Galectin-9 as an immunomodulator of B-cell activity
血管 Galectin-9 作为 B 细胞活性免疫调节剂的分析
基本信息
- 批准号:9981626
- 负责人:
- 金额:$ 20.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-15 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAdhesivesAntibodiesAntibody FormationAntibody ResponseAntigensAttenuatedAttenuated VaccinesAutoimmune DiseasesAutomobile DrivingB Cell ProliferationB-Cell ActivationB-Lymphocyte SubsetsB-LymphocytesBindingBiological AssayBiologyBlood VesselsCD22 geneCarbohydratesCartoonsCell AdhesionCell Adhesion MoleculesCell CommunicationCell modelCell surfaceCellsDataDevelopmentEndothelial CellsEndotheliumFoundationsGalactose Binding LectinGalactosidesGenesGoalsGrantHigh Endothelial VenuleHomeostasisHomingHumanImmuneImmune responseImmunityImmunologyImmunomodulatorsIn SituInfectionInhibition of Cell ProliferationInvestigationKnowledgeLaboratoriesLeadLectinLeukocytesLigandsLupusMediator of activation proteinMemoryMemory B-LymphocyteMethodsModelingMolecularMusMutant Strains MiceN-acetyllactosaminePTPN6 genePeripheralPhysiologicalPlasma CellsPolysaccharidesPositioning AttributeProteinsProtocols documentationPublishingReceptors, Antigen, B-CellRegulationRoleSignal TransductionStructureStructure of germinal center of lymph nodeSupporting CellTherapeuticTissuesTonsilVaccinationVascular Endothelial Cellblood groupcytokineexperiencehigh riskimmunoregulationin vivoinnovationinsightlymph nodeslymphoid organmouse modelnovelnovel therapeuticsperipheral tolerancerecruitsecondary lymphoid organtherapy designtranscriptome sequencing
项目摘要
PROJECT ABSTRACT
Development of effective antibody (Ab) responses is critically dependent on the recruitment of naïve B cells
into secondary lymphoid organs and, upon antigen activation, their coordinated differentiation into germinal
center (GC) B cells to memory B cells and Ab-producing plasma cells. Knowing which mechanistic factors
control B cell subset transition with the therapeutic goal of Ab-boosting or -attenuating activity, however, is still
poorly understood. Exciting new published data from our laboratory highlight striking differences in the
glycomic signatures of human naïve, GC and memory B cell subsets featured by either i-linear or I-branched
poly-N-acetyllactosamines (poly-LacNAcs). Whereas GC B cells express mainly I-branched poly-LacNAcs,
naïve/memory B cells display principally i-linear poly-LacNAcs, which enable robust binding to immuno-
modulator, galectin (Gal)-9. Gal-9-binding causes downstream inhibition of cell proliferation, activation and
signaling related to BCR-engagement while, interestingly, evoking a pro-survival activity. Given the selective
Gal-9-binding to naive/memory B cells, we speculate that Gal-9 serves as a physiologic “tuner” of peripheral B
cell activation and B cell reactivity. Other key data on the distribution of Gal-9 in “reactive” lymph node (LN)-
like tonsil tissue reveal that, while naïve B cells express endogenous Gal-9, Gal-9 expression is strongest on
high endothelial venules (HEV). Since HEVs initiate adhesive contact with circulating naïve/memory B cells
and are densely packed in the cortex adjacent to B cell follicles, HEVs are strategically poised to elicit Gal-9-
dependent adhesion/regulation. The spatial, cellular and functional control of Gal-9 on B cells in lymphoid
organs is still unknown and a major gap in the field of galectin immunology. Our guiding hypothesis is that Gal-
9 on HEV can bind circulating naïve/memory B cells and help recruit them into LNs as well as transmit
regulatory signals as B cells traverse the endothelium and enter B cell follicles. In this exploratory proposal,
we will examine the function of human endothelial cell (EC)-derived Gal-9 on human naïve B cell adhesion and
immunoregulation and will assay for B cell homing to peripheral LNs in the presence/absence of Gal-9. The
Specific Aims are: 1.) To study Gal-9-dependent vascular EC – B cell adhesive interactions and 2.) To
analyze immunoregulatory effects of Gal-9 expressed by cytokine-activated human ECs on human
naïve B cells. We will employ our unique experience and innovative primary human cell models, adhesion
assays, mutant mice, gene editing methods to study whether Gal-9 on ECs supports naïve B cell adhesion,
LN-homing as well as trigger immunoregulatory activity. These exploratory studies directly challenge current
dogma that galectins largely function as immunoregulators, offering an alternative role for Gal-9 in facilitating B
cell-EC adhesion, LN-homing and in situ peripheral control of B cell activity. Importantly, our findings will
reveal novel targets for modulating B cell immunity and provide necessary data for a grant larger in scope.
项目摘要
有效抗体(Ab)应答的产生严重依赖于幼稚B细胞的募集
进入次级淋巴器官,并在抗原激活后,它们协调分化为胚细胞
中心(GC)B细胞到记忆B细胞和产生Ab的浆细胞。了解哪些机械因素
然而,具有Ab-增强或-减弱活性的治疗目标的对照B细胞亚群转变仍然是
不太了解。来自我们实验室的令人兴奋的新发表数据突出了
人幼稚、GC和记忆B细胞亚群的糖组学特征,特征为i-线性或I-分支
聚-N-乙酰基乳糖胺(聚-LacNAc)。而GC B细胞主要表达I-分支的聚-LacNAc,
幼稚/记忆B细胞主要显示i-线性多聚LacNAc,其能够与免疫球蛋白牢固结合。
半乳糖凝集素(Gal)-9。Gal-9结合引起下游细胞增殖、活化和增殖的抑制。
与BCR接合相关的信号传导,同时有趣的是,引起促存活活性。鉴于选择性
Gal-9与幼稚/记忆B细胞结合,我们推测Gal-9作为外周B细胞的生理“调谐器
细胞活化和B细胞反应性。关于Gal-9在“反应性”淋巴结(LN)中分布的其他关键数据-
类似扁桃体组织显示,虽然幼稚B细胞表达内源性Gal-9,但Gal-9表达在
高内皮微静脉(HEV)。由于HEV启动与循环幼稚/记忆B细胞的粘附接触
并且密集地堆积在邻近B细胞滤泡的皮质中,HEV策略性地准备好引发Gal-9-
依赖性粘附/调节。Gal-9对淋巴细胞中B细胞的空间、细胞和功能调控
器官仍然是未知的,并且是半乳糖凝集素免疫学领域的主要空白。我们的指导假设是加尔-
HEV上的9可以结合循环中的幼稚/记忆B细胞,并帮助将它们招募到LN中,
当B细胞穿过内皮并进入B细胞滤泡时,调节信号。在这个探索性的提议中,
我们将检测人内皮细胞(EC)衍生的Gal-9对人幼稚B细胞粘附的功能,
免疫调节,并将在存在/不存在Gal-9的情况下测定B细胞归巢至外周LN。的
具体目标是:(1)研究Gal-9依赖的血管EC - B细胞粘附相互作用和2.)到
分析由精氨酸活化的人EC表达的Gal-9对人的免疫调节作用。
幼稚B细胞。我们将利用我们独特的经验和创新的原代人类细胞模型,
测定、突变小鼠、研究EC上的Gal-9是否支持幼稚B细胞粘附的基因编辑方法,
LN归巢以及触发免疫调节活性。这些探索性研究直接挑战了当前
半乳糖凝集素在很大程度上起免疫调节剂的作用,为Gal-9在促进B中提供了替代作用
细胞-EC粘附、LN归巢和B细胞活性的原位外周控制。重要的是,我们的发现将
揭示了调节B细胞免疫的新靶点,并为更大范围的资助提供了必要的数据。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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CHARLES J DIMITROFF的其他文献
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{{ truncateString('CHARLES J DIMITROFF', 18)}}的其他基金
Analysis of Glycomic Regulators in Melanoma Progression
黑色素瘤进展中的糖调节因子分析
- 批准号:
10086171 - 财政年份:2019
- 资助金额:
$ 20.47万 - 项目类别:
Analysis of Glycomic Regulators in Melanoma Progression
黑色素瘤进展中的糖调节因子分析
- 批准号:
10611441 - 财政年份:2019
- 资助金额:
$ 20.47万 - 项目类别:
Analysis of Glycomic Regulators in Melanoma Progression
黑色素瘤进展中的糖调节因子分析
- 批准号:
10414886 - 财政年份:2019
- 资助金额:
$ 20.47万 - 项目类别:
Analysis of Glycomic Regulators in Melanoma Progression
黑色素瘤进展中的糖调节因子分析
- 批准号:
9886212 - 财政年份:2019
- 资助金额:
$ 20.47万 - 项目类别:
Analysis of vascular Galectin-9 as an immunomodulator of B-cell activity
血管 Galectin-9 作为 B 细胞活性免疫调节剂的分析
- 批准号:
9807300 - 财政年份:2019
- 资助金额:
$ 20.47万 - 项目类别:
Functional Analysis of Galectin-1 Ligands in Melanoma Progression
Galectin-1 配体在黑色素瘤进展中的功能分析
- 批准号:
8693969 - 财政年份:2013
- 资助金额:
$ 20.47万 - 项目类别:
Functional Analysis of Galectin-1 Ligands in Melanoma Progression
Galectin-1 配体在黑色素瘤进展中的功能分析
- 批准号:
9265414 - 财政年份:2013
- 资助金额:
$ 20.47万 - 项目类别:
Functional Analysis of Galectin-1 Ligands in Melanoma Progression
Galectin-1 配体在黑色素瘤进展中的功能分析
- 批准号:
8578572 - 财政年份:2013
- 资助金额:
$ 20.47万 - 项目类别:
Mechanistic Analysis of Anti-inflammatory Activity by Fluorosugars
氟糖抗炎活性的机制分析
- 批准号:
8007408 - 财政年份:2008
- 资助金额:
$ 20.47万 - 项目类别:
Mechanistic Analysis of Anti-inflammatory Activity by Fluorosugars
氟糖抗炎活性的机制分析
- 批准号:
8215806 - 财政年份:2008
- 资助金额:
$ 20.47万 - 项目类别:
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