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
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)
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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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