B cell costimulatory signals in the pathogenesis of SLE
SLE 发病机制中的 B 细胞共刺激信号
基本信息
- 批准号:10424655
- 负责人:
- 金额:$ 10.55万
- 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:2019-08-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnatomyAnimal ModelAntigen PresentationAntinuclear AntibodiesAutoantibodiesAutoantigensAutoimmuneAutoimmune DiseasesAutoimmune ResponsesAutoimmunityAutomobile DrivingB-Cell ActivationB-Cell Antigen ReceptorB-LymphocytesBiologyCD19 geneCD28 geneCD4 Positive T LymphocytesCD80 geneCD86 geneCTLA4-IgCell SurvivalCellsChronicChronic Childhood ArthritisClinicalClinical TrialsComplexDataDevelopmentDiseaseEpitopesEventFDA approvedFamilyFutureGenerationsGoalsHumanHumoral ImmunitiesImmuneImmune ToleranceImmune responseImmune signalingImmunityImmunoglobulin Class SwitchingImmunoglobulin Somatic HypermutationImmunohistochemistryKnowledgeLigandsLinkLocationLongitudinal StudiesLupusLupus NephritisMHC Class II GenesMaintenanceModelingModernizationMusMutation AnalysisNuclear AntigensOrganOutputPathogenesisPathogenicityPathway interactionsPatientsPlasma CellsProductionRNARandomized Clinical TrialsResearchRheumatoid ArthritisRoleSerumSignal TransductionSpecificityStructure of germinal center of lymph nodeSystemic Lupus ErythematosusT-Cell ActivationT-LymphocyteTechnologyTestingTherapeuticTherapeutic immunosuppressionautoreactive B cellbasechimeric antigen receptor T cellsclinical efficacydesigndisorder controlds-DNAexperimental studyhigh riskimprovedinsightmigrationnovelnovel therapeuticspathogenic autoantibodiespre-clinicalpreservationreceptorresponsesystemic autoimmune diseasetargeted treatmenttool
项目摘要
Project abstract
Despite modern immunosuppressive therapies, patients with systemic lupus erythematosus (SLE) remain at
high risk for progressive organ damage, emphasizing the need for better, targeted treatments for this disease.
In addition to the production of pathogenic autoantibodies, recent studies have demonstrated that B cells can
promote lupus pathogenesis by initiating immune tolerance breaks and facilitating the generation of
spontaneous germinal centers (GC). In this context, distinct costimulatory receptor families have been linked
with the pathogenesis of autoimmunity. However, despite compelling preclinical data in SLE and clinical benefit
in other autoimmune diseases, costimulatory blockade with CTLA4-Ig (Abatacept) failed to control disease in
lupus clinical trials. These data emphasize that our understanding of the cell-intrinsic mechanisms whereby
B7:CD28 costimulatory signals impact autoreactive B cell activation in lupus is incomplete. In this project, we
will use well-characterized murine lupus models and the novel application of chimeric antigen receptor (CAR) T
cell technology to dissect the immune mechanisms underlying the initiation, propagation and cellular output of
extra-follicular (EF) vs. GC B cell activation pathways in SLE. In Aim 1, we will study whether pathogenic
autoantibodies can be generated via an EF B cell activation pathway in a T cell-dependent, but CD28
independent, manner. In Aim 2, we will test whether B cell costimulatory signals promote the initiation or
maintenance of autoimmune GC responses. Finally, in Aim 3, we will test whether another costimulatory
receptor pair, ICOS:ICOS ligand, compensates for loss of CD28 signals during lupus pathogenesis. Together,
these studies promise to advance our understanding of lupus pathogenesis and may inform the design of
future human clinical trials of costimulatory blockade in SLE and other humoral autoimmune diseases.
项目摘要
尽管现代免疫抑制疗法,系统性红斑狼疮(SLE)患者仍处于
进行性器官损害的高风险,强调需要对这种疾病进行更好的、有针对性的治疗。
除了产生致病的自身抗体外,最近的研究表明B细胞可以
通过启动免疫耐受破坏和促进狼疮的产生来促进狼疮的发病
自发生发中心(GC)。在这种背景下,不同的共刺激受体家族被联系在一起
与自身免疫的发病机制有关。然而,尽管系统性红斑狼疮的临床前数据和临床益处令人信服
在其他自身免疫性疾病中,用CTLA4-Ig(Abatacept)共刺激阻断未能控制疾病
狼疮临床试验。这些数据强调,我们对细胞内在机制的理解
B7:CD28共刺激信号在狼疮中影响自身反应性B细胞激活是不完整的。在这个项目中,我们
将使用特征良好的小鼠狼疮模型和嵌合抗原受体(CAR)T的新应用
细胞技术,剖析引发、繁殖和细胞输出的免疫机制
系统性红斑狼疮的卵泡外(EF)与GC B细胞激活途径。在目标1中,我们将研究致病因素
自身抗体可以通过T细胞依赖的EF B细胞激活途径产生,但CD28
独立的,举止的。在目标2中,我们将测试B细胞共刺激信号是否促进
维持自身免疫性GC反应。最后,在目标3中,我们将测试另一个共刺激
受体对,ICOS:ICOS配体,在狼疮发病过程中补偿CD28信号的丢失。一起,
这些研究有望促进我们对狼疮发病机制的理解,并可能为设计
未来共刺激阻断治疗系统性红斑狼疮和其他体液自身免疫性疾病的临床试验。
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)
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Shaun William Jackson其他文献
Shaun William Jackson的其他文献
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{{ truncateString('Shaun William Jackson', 18)}}的其他基金
Impact of Loss-of-function NADPH Oxidase Variants on B cell Activation in SLE
功能丧失的 NADPH 氧化酶变体对 SLE 中 B 细胞激活的影响
- 批准号:
10577834 - 财政年份:2021
- 资助金额:
$ 10.55万 - 项目类别:
B cell costimulatory signals in the pathogenesis of SLE
SLE 发病机制中的 B 细胞共刺激信号
- 批准号:
10670450 - 财政年份:2019
- 资助金额:
$ 10.55万 - 项目类别:
B cell costimulatory signals in the pathogenesis of SLE
SLE 发病机制中的 B 细胞共刺激信号
- 批准号:
10169781 - 财政年份:2019
- 资助金额:
$ 10.55万 - 项目类别:
B cell costimulatory signals in the pathogenesis of SLE
SLE 发病机制中的 B 细胞共刺激信号
- 批准号:
10208723 - 财政年份:2019
- 资助金额:
$ 10.55万 - 项目类别:
B cell costimulatory signals in the pathogenesis of SLE
SLE 发病机制中的 B 细胞共刺激信号
- 批准号:
9982781 - 财政年份:2019
- 资助金额:
$ 10.55万 - 项目类别:
B cell costimulatory signals in the pathogenesis of SLE
SLE 发病机制中的 B 细胞共刺激信号
- 批准号:
10434892 - 财政年份:2019
- 资助金额:
$ 10.55万 - 项目类别:
B cell-intrinsic cytokine regulation and B cell-targeted therapies in murine lupu
小鼠狼疮中的 B 细胞内在细胞因子调节和 B 细胞靶向治疗
- 批准号:
8871563 - 财政年份:2014
- 资助金额:
$ 10.55万 - 项目类别:
B cell-intrinsic cytokine regulation and B cell-targeted therapies in murine lupu
小鼠狼疮中的 B 细胞内在细胞因子调节和 B 细胞靶向治疗
- 批准号:
9085227 - 财政年份:2014
- 资助金额:
$ 10.55万 - 项目类别:
B cell-intrinsic cytokine regulation and B cell-targeted therapies in murine lupu
小鼠狼疮中的 B 细胞内在细胞因子调节和 B 细胞靶向治疗
- 批准号:
8759642 - 财政年份:2014
- 资助金额:
$ 10.55万 - 项目类别:
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