Characterization of E. coli-specific T cells in Crohn's disease
克罗恩病中大肠杆菌特异性 T 细胞的表征
基本信息
- 批准号:10452471
- 负责人:
- 金额:$ 25.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnti-Inflammatory AgentsAntibodiesAntigen ReceptorsAntigensBacteriaCD4 Positive T LymphocytesCellsChromatinChromatin StructureChronic DiseaseClinicColonCore FacilityCrohn&aposs diseaseData SetDefectDiseaseEnterocolitisEpigenetic ProcessEquilibriumEscherichia coliEscherichia coli ProteinsExploratory/Developmental GrantFoundationsFundingFutureGastroenterologyGastrointestinal tract structureGene ExpressionGenesGenomicsGenotypeGoalsHepatitis B e AntigensHomeostasisHumanImmuneImmune ToleranceImmune systemImmunoglobulin AImmunologyIndividualInflammationInflammatoryInflammatory Bowel DiseasesInstitutesInstitutionInterleukin-10IntestinesMeasuresModelingMolecularMusMutationPathogenesisPatientsPeptidesPersonsPhenotypePlayPositioning AttributeProductionProteinsReactionRegulationResearchResearch PersonnelRestRoleSamplingSystemic TherapyT cell regulationT-LymphocyteTechnologyTranslational ResearchWorkantigen-specific T cellsbasebiobankcohortcytokinegenome-widegut inflammationgut microbiomegut microbiotahigh dimensionalityhigh rewardinsightmicrobiomemicroorganism antigennovel strategiespreventprospectivereceptorrecruitresponsetranscriptome sequencingtranscriptomics
项目摘要
PROJECT SUMMARY/ABSTRACT
Several lines of evidence have implicated T cells in the pathogenesis of Crohn's disease, an uncontrolled
inflammatory condition of the intestines in which immune cells overreact to the bacteria that live there.
Previous studies of antigen-nonspecific T cells in Crohn's disease have not identified overall differences in
them that would explain this over reactivity. However, we have recently identified CD4 T cells of the immune
system that can react to a peptide from protein antigen (OmpC) made by one such bacteria (E. coli), to which
antibodies are commonly seen only in people with Crohn's disease. We found that these OmpC-specific cells
make IL-10 unless they come from Crohn's disease patients, and hypothesize that this defect plays a central
role in the inflammation of Crohn's disease. IL-10 is a cytokine that clearly plays a central role in limiting
inflammation in the intestines, because mice without the IL-10 gene and humans born with a mutation in the
receptor for IL-10 both quickly develop severe enterocolitis, resembling Crohn's disease. The overall goal of
the studies proposed here is to determine why these gut flora antigen-specific T cells fail to make IL-10 in
Crohn's disease, as a mechanism by which tolerance to gut flora is lost in this condition. The novel approach
is to integrate single cell gene expression and epigenetic analyses in these OmpC-specific T cells we can
isolate with MHC-II tetramers. The hypothesis will be addressed in two Specific Aims with genome-wide
expression differences correlated with IL-10 expression in Aim 1, and an epigenetic basis for failed IL-10
expression in Crohn's disease to be revealed in Aim 2. Together these studies will advance our understanding
of abnormal IL-10 regulation by gut microbial antigen-specific T cells in Crohn's disease, and provide the
foundation for determining how such a defect contributes to disease pathogenesis.
项目总结/摘要
几条证据表明T细胞参与了克罗恩病的发病机制,克罗恩病是一种无法控制的疾病,
肠道的炎症状态,免疫细胞对肠道内的细菌反应过度。
以前对克罗恩病中抗原非特异性T细胞的研究尚未确定
他们可以解释这种过度反应。然而,我们最近发现了免疫系统中的CD 4 T细胞,
可以与来自蛋白质抗原(OmpC)的肽反应的系统(E.大肠杆菌),其中
抗体通常只在克罗恩病患者中可见。我们发现这些OmpC特异性细胞
除非它们来自克罗恩病患者,否则它们不会产生IL-10,并假设这种缺陷在克罗恩病患者中起着核心作用。
在克罗恩病炎症中的作用。IL-10是一种细胞因子,其在限制肿瘤细胞增殖中明显起着核心作用。
肠道炎症,因为没有IL-10基因的小鼠和出生时具有IL-10基因突变的人类,
IL-10受体的受试者都迅速发展为严重的小肠结肠炎,类似于克罗恩病。的总目标
这里提出的研究是要确定为什么这些肠道植物群抗原特异性T细胞不能产生IL-10,
克罗恩病,作为一种机制,其中耐受肠道植物群是在这种情况下失去。这种新方法
是在这些OmpC特异性T细胞中整合单细胞基因表达和表观遗传分析,
用MHC-II四聚体分离。这一假设将在两个特定的目的与全基因组
表达差异与Aim 1中IL-10表达相关,以及IL-10失败的表观遗传基础
在克罗恩病中的表达将在Aim 2中揭示。这些研究将共同推进我们对
肠道微生物抗原特异性T细胞对克罗恩病中IL-10的异常调节,
确定这种缺陷如何有助于疾病发病机制的基础。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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{{ truncateString('James Daniel Lord', 18)}}的其他基金
Characterization of E. coli-specific T cells in Crohn's disease
克罗恩病中大肠杆菌特异性 T 细胞的表征
- 批准号:
10558631 - 财政年份:2022
- 资助金额:
$ 25.95万 - 项目类别:
Intestinal Dendritic Cell Modulation of Regulatory T Cell Function in IBD
IBD 中调节性 T 细胞功能的肠道树突状细胞调节
- 批准号:
8141666 - 财政年份:2008
- 资助金额:
$ 25.95万 - 项目类别:
Intestinal Dendritic Cell Modulation of Regulatory T Cell Function in IBD
IBD 中调节性 T 细胞功能的肠道树突状细胞调节
- 批准号:
7808332 - 财政年份:2008
- 资助金额:
$ 25.95万 - 项目类别:
Intestinal Dendritic Cell Modulation of Regulatory T Cell Function in IBD
IBD 中调节性 T 细胞功能的肠道树突状细胞调节
- 批准号:
7513622 - 财政年份:2008
- 资助金额:
$ 25.95万 - 项目类别:
Intestinal Dendritic Cell Modulation of Regulatory T Cell Function in IBD
IBD 中调节性 T 细胞功能的肠道树突状细胞调节
- 批准号:
8077443 - 财政年份:2008
- 资助金额:
$ 25.95万 - 项目类别:
Intestinal Dendritic Cell Modulation of Regulatory T Cell Function in IBD
IBD 中调节性 T 细胞功能的肠道树突状细胞调节
- 批准号:
8317680 - 财政年份:2008
- 资助金额:
$ 25.95万 - 项目类别:
Intestinal Dendritic Cell Modulation of Regulatory T Cell Function in IBD
IBD 中调节性 T 细胞功能的肠道树突状细胞调节
- 批准号:
7676870 - 财政年份:2008
- 资助金额:
$ 25.95万 - 项目类别:
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