B Cells and Type 1 Diabetes
B 细胞和 1 型糖尿病
基本信息
- 批准号:9104150
- 负责人:
- 金额:$ 32.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-08-20 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityAmericanAntigen PresentationAntigen ReceptorsAntigensAutoantibodiesAutoimmune DiseasesAutoimmunityB-Cell ActivationB-LymphocytesBone MarrowCD4 Positive T LymphocytesCell physiologyCell surfaceCellsClinical TrialsDevelopmentDiabetes MellitusDiabetic mouseDiseaseEducational process of instructingFirst Degree RelativeFlow CytometryFrequenciesGene Transfer TechniquesGoalsHeavy-Chain ImmunoglobulinsHumanImmuneImmune ToleranceImmune systemInbred NOD MiceIndividualInjuryInsulinInsulin-Dependent Diabetes MellitusKnowledgeLaboratoriesLymphoidMS4A1 geneMediatingModelingMusOrganPancreasPeripheralPhenotypePopulationPredispositionRoleSignal PathwaySpleenSurfaceT-LymphocyteTechniquesTestingTo autoantigenTreatment EfficacyWorkadaptive immunityanergybasecell typecentral tolerancediabeticdiabetic patientdiabetogenicfunctional statusinsulin dependent diabetes mellitus onsetmagnetic beadsnon-diabeticnovelpreventresearch studytargeted treatmenttherapeutic effectiveness
项目摘要
DESCRIPTION (provided by applicant): Autoimmunity affects nearly ten million Americans and, for unknown reasons, is increasing in frequency. Available evidence indicates that autoimmune diseases arise due to a combination of genetically determined susceptibility and innate immune stimulation, which conspire to stimulate adaptive immunity to self. Underpinning autoimmunity is the breakdown of immune tolerance to self in T cell and/or B cell compartments. While a great deal is known about the mechanisms that maintain B cell tolerance, we understand little about the mechanisms that cause it to fail in autoimmunity. In this application we propose to study mechanisms operative in loss of B cell tolerance to insulin in murine and human Type 1 Diabetes, a disease known to require B cells that are thought to function by antigen presentation to CD4 T cells. Our approach will build upon our previous work defining signaling pathways operative in maintaining antigen unresponsiveness of anergic B cells. We will analyze by flow cytometry changes in the status of insulin-specific B cells isolated using a novel magnetic bead-based approach from normal, prediabetic and diabetic mice and patients. In some cases immunoglobulin heavy chain transgenesis will be used to generate a diverse antigen receptor repertoire that is nonetheless enriched in insulin-specific cells. Aim 1 will explore how peripheral insulin-specific B cells are silenced in normal mice and whether this silencing is breached in diabetic mice. In Aim 2 we will study the role of antigen receptor affinit for insulin in determining mode of silencing, fate and diabetogenic potential. This will involve a retrotransgenic approach to generate a repertoire with defined antigen receptor affinity for insulin. In Aim 3 we will extend studies to the human, comparing insulin-specific B cells in prediabetic and diabetic individuals to non-diabetic first- degree relatives. Finally, in Aim 4 we will assess the therapeutic efficacy in T1D of a novel B cell desensitizing therapy, comparing this therapy to anti-CD20, which depletes B cells. The experiments will address the overarching hypothesis that in Type 1 Diabetes the silence of high affinity insulin-specific B cells is broken and these cells promote disease by presentation of autoantigen to CD4 T cells.
描述(由申请人提供):自身免疫会影响近一千万美国人,由于未知原因,频率的增加。可用的证据表明,自身免疫性疾病是由于遗传确定的易感性和先天免疫刺激的结合而引起的,这些易感性刺激了刺激自我的适应性免疫。自身免疫的基础是T细胞和/或B细胞室中对自我的免疫耐受性的破坏。虽然对维持B细胞耐受性的机制有很多了解,但我们对导致自身免疫性失败的机制知之甚少。在此应用中,我们建议研究在鼠类和人类1型糖尿病中损失B细胞胰岛素的机制,该疾病已知需要B细胞,这些疾病被认为是通过抗原表现出对CD4 T细胞的作用的。我们的方法将基于我们以前的工作定义信号通路,以维持抗原B细胞的抗原无反应性。我们将通过流式细胞仪的变化在胰岛素特异性B细胞状态的状态下,使用从正常,糖尿病前和糖尿病小鼠以及患者的基于磁珠的新方法分离的胰岛素特异性B细胞状态。在某些情况下,免疫球蛋白重链转基因将用于产生多种抗原受体库,尽管如此,该抗原受体库仍富含胰岛素特异性细胞。 AIM 1将探索正常小鼠外周胰岛素特异性B细胞的沉默以及该沉默是否在糖尿病小鼠中破坏。在AIM 2中,我们将研究抗原受体亲和胰岛素在确定沉默,命运和糖尿病生成潜力模式中的作用。这将涉及一种逆转录的方法,以产生具有定义的抗原受体亲和力的曲目。在AIM 3中,我们将将研究扩展到人类,将糖尿病前和糖尿病个体的胰岛素特异性B细胞与非糖尿病的一级亲戚进行比较。最后,在AIM 4中,我们将评估一种新型B细胞脱敏治疗的T1D的治疗功效,将这种疗法与抗CD20进行比较,抗CD20耗尽了B细胞。实验将解决以下总体假设:在1型糖尿病中,高亲和胰岛素特异性B细胞的沉默被破坏,这些细胞通过将自动抗原呈现给CD4 T细胞来促进疾病。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Activation of thyroid antigen-reactive B cells in recent onset autoimmune thyroid disease patients.
- DOI:10.1016/j.jaut.2017.12.001
- 发表时间:2018-05
- 期刊:
- 影响因子:12.8
- 作者:Smith MJ;Rihanek M;Coleman BM;Gottlieb PA;Sarapura VD;Cambier JC
- 通讯作者:Cambier JC
Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy.
- DOI:10.3389/fimmu.2018.00665
- 发表时间:2018
- 期刊:
- 影响因子:7.3
- 作者:Franks SE;Cambier JC
- 通讯作者:Cambier JC
B cells in type 1 diabetes mellitus and diabetic kidney disease.
- DOI:10.1038/nrneph.2017.138
- 发表时间:2017-10-17
- 期刊:
- 影响因子:0
- 作者:Smith MJ;Simmons KM;Cambier JC
- 通讯作者:Cambier JC
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John C Cambier其他文献
John C Cambier的其他文献
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{{ truncateString('John C Cambier', 18)}}的其他基金
Autoimmunity risk alleles compromising B cell anergy
损害 B 细胞无反应性的自身免疫风险等位基因
- 批准号:
9568080 - 财政年份:2016
- 资助金额:
$ 32.51万 - 项目类别:
Autoimmunity risk alleles compromising B cell anergy
损害 B 细胞无反应性的自身免疫风险等位基因
- 批准号:
9121221 - 财政年份:2016
- 资助金额:
$ 32.51万 - 项目类别:
Insulin Specific T and B cells in Type 1 Diabetes
1 型糖尿病中的胰岛素特异性 T 细胞和 B 细胞
- 批准号:
9180031 - 财政年份:2016
- 资助金额:
$ 32.51万 - 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
- 批准号:
8282484 - 财政年份:2012
- 资助金额:
$ 32.51万 - 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
- 批准号:
8519291 - 财政年份:2012
- 资助金额:
$ 32.51万 - 项目类别:
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