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:10558631
- 负责人:
- 金额:$ 21.66万
- 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 ExpressionGenomicsGenotypeGoalsHomeostasisHumanIL10 geneImmuneImmune ToleranceImmune systemImmunoglobulin AImmunologyIndividualInflammationInflammatoryInflammatory Bowel DiseasesInstitutionInterleukin-10IntestinesMeasuresModelingMolecularMusMutationPathogenesisPatientsPeptidesPersonsPhenotypePlayPositioning AttributeProductionProteinsQualifyingReactionRegulationResearchResearch PersonnelRestRoleSamplingSystemic TherapyT cell regulationT-LymphocyteTechnologyTranslational ResearchWorkantigen-specific T cellsbiobankcohortcytokinegenome-widegut inflammationgut microbiomegut microbiotahigh dimensionalityhigh rewardinsightinterleukin-10 receptormicrobiomemicroorganism antigennovel strategiespreventprospectiverecruitresponsetranscriptome 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.
项目摘要/摘要
有几条证据表明T细胞与克罗恩病的发病有关,克罗恩病是一种未受控制的
肠道的一种炎症状态,免疫细胞对生活在那里的细菌反应过度。
以前对克罗恩病的抗原非特异性T细胞的研究还没有发现在
他们可以解释这种反应过度的现象。然而,我们最近发现了免疫的CD4T细胞
一种能与由这样一种细菌(大肠杆菌)产生的蛋白质抗原(OMPC)中的多肽发生反应的系统,对其
抗体通常只出现在克罗恩病患者身上。我们发现这些OMPC特异性细胞
产生IL-10,除非他们来自克罗恩病患者,并假设这种缺陷在
在克罗恩病炎症中的作用。IL-10是一种细胞因子,显然在限制
肠道炎症,因为没有IL-10基因的小鼠和出生时携带IL-10基因突变的人类
IL-10的受体都会迅速发展成严重的小肠结肠炎,类似于克罗恩病。的总目标是
这里提出的研究是为了确定为什么这些肠道菌群抗原特异的T细胞无法在
克罗恩病,是一种在这种情况下对肠道菌群失去耐受性的机制。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学分析,我们可以
用MHC-II四聚体分离。这一假说将在全基因组范围内以两个特定的目标来解决
AIM 1的表达差异与IL-10的表达相关,并为失败的IL-10的表观遗传学基础
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的理解
克隆氏病患者肠道微生物抗原特异性T细胞对IL-10的异常调节
为确定这种缺陷如何导致疾病发病机制奠定了基础。
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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James Daniel Lord其他文献
James Daniel Lord的其他文献
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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:
10452471 - 财政年份:2022
- 资助金额:
$ 21.66万 - 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:
$ 21.66万 - 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:
$ 21.66万 - 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:
$ 21.66万 - 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:
$ 21.66万 - 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:
$ 21.66万 - 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:
$ 21.66万 - 项目类别:
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