Heterogeneous pathways to autoantibody production: implications for prognosis and therapeutic targeting
自身抗体产生的异质途径:对预后和治疗靶向的影响
基本信息
- 批准号:10159859
- 负责人:
- 金额:$ 31.98万
- 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:2019-05-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:Adaptive Immune SystemAddressAffectAntibodiesAnticardiolipin AntibodiesAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmunityB-Cell ActivationB-LymphocytesBiologicalCell ProliferationCell physiologyCellsCellular Metabolic ProcessClinicalClinical TrialsClonal ExpansionCollaborationsData AnalysesDiagnosisDiamondDiseaseEnsureEnvironmental ExposureFDA approvedFailureFlareFluorescenceGene Expression ProfileGenerationsGenetic TranscriptionHealth Care CostsHelper-Inducer T-LymphocyteHeterogeneityHomeostasisHumanImmuneImmune responseImmunocompetenceImmunoglobulin GenesImmunologic MemoryImmunologicsIncidenceIndividualInflammationInflammatory ArthritisInstitutesInterventionKnowledgeLabelLeadLupusMedical ResearchMetabolicMethodsMilitary PersonnelMorbidity - disease rateNuclear AntigensOnset of illnessOrganOutcomePathogenesisPathologicPathologyPathway interactionsPatient RecruitmentsPatient SelectionPatientsPharmaceutical PreparationsPhasePhase II/III TrialPilot ProjectsPlasma CellsPlasmablastPopulationPreparationPrevalenceProductionPrognosisQuality of lifeReagentRegulationResearch PersonnelRheumatoid ArthritisRiskSerumSourceSystemic Lupus ErythematosusSystemic TherapyT-LymphocyteTNF geneTechnologyThe SunTherapeuticTimeTissuesToxic effectWomanautoreactive B cellautoreactivityclinical infrastructurecostdesignds-DNAgenetic risk factorimprovedindividual patientinhibitor/antagonistinterestmicrobialmicroorganism antigenmortalitymouse modelnew technologynext generation sequencingnovelnovel therapeuticspatient stratificationperipheral bloodpersonalized medicinepre-clinicalpreventprogramsside effectsuccesstherapeutic targettherapeutically effectivetissue injurytool
项目摘要
Project Summary/Abstract
Systemic lupus erythematosus (SLE) is a devastating autoimmune disease in which autoantibodies to ubiquitous
nuclear antigens cause inflammation and tissue damage in multiple organs. The treatment of SLE has improved
considerably over the past 30 years, but these advances have relied on existing medications with insufficient
efficacy and significant toxicities. Although several new therapeutics are advancing to Phase 2 and 3 trials, only
one modestly effective biologic is currently FDA approved for treating active SLE. It is imperative, therefore, that
advances in immunologic knowledge be applied to improve the treatment and quality of life of SLE patients.
Autoantibody production is central to the pathogenesis of SLE but many questions remain about the origins of
the plasma cells that produce them. It is clear that autoantibody production can precede disease onset by many
years, and that flares of SLE are often associated with a new wave of plasma cell proliferation. Our Autoimmunity
Center of Excellence proposal is centered on the hypothesis that an improved understanding of the mechanisms
of induction and source of autoantibodies in individual patients will allow us to define the spectrum of
dysregulated mechanisms responsible for loss of tolerance in human SLE and will form the basis for appropriate
patient stratification and selection for clinical trials. To this end, we will apply new technologies that allow
meaningful study of small numbers of human cells in a native repertoire to revisit basic questions about the origin
and regulation of autoantibodies in SLE. A crucial tool is a new fluorescent nuclear antigen preparation,
developed by the Diamond lab that can be used to identify and isolate autoreactive B cells that represent only a
small fraction of the total B cell population. This will facilitate the use next generation sequencing of
immunoglobulin genes to analyze the repertoire specifically of autoreactive B cells. The Principal Project will
characterize autoreactive plasma cells from patients with SLE and ask about their origins and transcriptional
profile, with a view to identifying distinct pathways of activation in individual patients that may be specific to
autoreactive B cells, compared with cells that protect against microbial antigens. The Collaborative Project will
examine mechanisms for the initiation of lupus-related autoimmunity in patients being treated with TNF inhibitors
for inflammatory arthritis. The Pilot Project will address the transcriptional, metabolic and functional diversity of
circulating T follicular helper cells in patients with SLE and ask whether it is possible to restore normal B cell
helper function of these cells by altering T cell metabolism. Our proposal is bolstered by close scientific
interactions among the three lead investigators, by collaborations with experts in next generation sequencing
methods and data analysis and by a robust clinical infrastructure that will add clinical depth and ensure timely
recruitment of patients for all three studies.
项目总结/文摘
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Anne Davidson其他文献
Anne Davidson的其他文献
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{{ truncateString('Anne Davidson', 18)}}的其他基金
Dissecting the heterogeneity and function of myeloid cells in lupus nephritis
剖析狼疮性肾炎骨髓细胞的异质性和功能
- 批准号:
10588862 - 财政年份:2023
- 资助金额:
$ 31.98万 - 项目类别:
T32 Training Grant in Translational Immunology
T32 转化免疫学培训补助金
- 批准号:
10470893 - 财政年份:2021
- 资助金额:
$ 31.98万 - 项目类别:
Mechanisms for Human TLR8 induced pregnancy loss in a mouse model of SLE
人 TLR8 诱导 SLE 小鼠模型妊娠失败的机制
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10301657 - 财政年份:2021
- 资助金额:
$ 31.98万 - 项目类别:
T32 Training Grant in Translational Immunology
T32 转化免疫学培训补助金
- 批准号:
10653079 - 财政年份:2021
- 资助金额:
$ 31.98万 - 项目类别:
Mechanisms for Human TLR8 induced pregnancy loss in a mouse model of SLE
人 TLR8 诱导 SLE 小鼠模型妊娠失败的机制
- 批准号:
10434117 - 财政年份:2021
- 资助金额:
$ 31.98万 - 项目类别:
Induction of lupus-related autoantibodies by TNF inhibitors
TNF 抑制剂诱导狼疮相关自身抗体
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10405223 - 财政年份:2021
- 资助金额:
$ 31.98万 - 项目类别:
T32 Training Grant in Translational Immunology
T32 转化免疫学培训补助金
- 批准号:
10269999 - 财政年份:2021
- 资助金额:
$ 31.98万 - 项目类别:
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