Identifying and preventing antigen specific T cells in diabetes
识别和预防糖尿病中的抗原特异性 T 细胞
基本信息
- 批准号:10634700
- 负责人:
- 金额:$ 59.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-22 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AntibodiesAntigensAutoantibodiesAutoimmuneAutoimmune DiabetesAutoimmune DiseasesB-LymphocytesBeta CellBiological MarkersBlocking AntibodiesCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell DeathCell SeparationCellsCoupledDevelopmentDiabetes MellitusDiabetes preventionDiabetic mouseDisease ProgressionEarly DiagnosisFingerprintFrequenciesFunctional disorderGene Expression ProfileGenetic TranscriptionGoalsGrantHumanHybridsImmune ToleranceIn VitroInbred NOD MiceIndividualInsulinInsulin-Dependent Diabetes MellitusKnowledgeMediatingModelingMouse StrainsMusNon obeseOnset of illnessPancreasPathogenesisPathogenicityPathway AnalysisPatientsPeptidesPeripheralPopulationPredispositionPreventionPreventive therapyProductionPropertyProteinsProtocols documentationReagentRegulatory T-LymphocyteResearchRiskRoleT cell differentiationT cell regulationT-Cell ReceptorT-LymphocyteTestinganergyantigen testantigen-specific T cellsautoreactivitycentral tolerancechimeric antigen receptordiabetes riskdiabeticeffective therapygenetic signatureinsulin dependent diabetes mellitus onsetisletislet cell antibodymemory CD4 T lymphocytemouse modelneoantigensnovel therapeutic interventionpreventprogramsscreeningsingle-cell RNA sequencingtargeted treatmenttraffickingtranscriptometype I diabetic
项目摘要
SUMMARY
Type 1 diabetes (T1D) is an autoimmune disease resulting from a breakdown in immunological
tolerance caused by T cell-mediated destruction of islet beta cells. Diabetes is orchestrated by HLAII-
restricted CD4+ T cells, through cellular interactions with both B cells and CD8+ T cells, resulting in
autoantibody production and beta cell death, respectively. While anti-islet autoantibodies are currently
the best predictors of T1D development, screening is limited to four islet antigens and no T cell
biomarkers exist. Despite years of research, it is still unclear which antigen-specific CD4+ T cells
initiate T1D. New evidence suggests that hybrid peptides (HP) formed from the fusion of islet β cell
proteins may be critical antigens in T1D as recent studies identified HP-reactive CD4+ T cells from
T1D patients and diabetic mice in vitro. These neo-antigens escape central tolerance and must be
controlled by peripheral mechanisms including anergy or regulatory T cell control. In preliminary
studies, we identified HP-specific CD4+ T cells in diabetic mouse models using tetramer reagents,
and showed they are pathogenic and cause T1D in mouse transfer models. More importantly, we can
block spontaneous T1D in the NOD mouse model targeting one hybrid peptide when presented in
mouse MHCII using peptide-specific:MHCII blocking antibodies. Thus, we hypothesize that HPs are
critical antigens and that autoreactivity to HPs initiates T1D. The goals of this proposal are to
determine if HP-specific CD4+ T cells initiate T1D and if targeting them can lead to tolerance as a
prevention or cure for T1D. The second goal of the grant is to determine if HP specific cells are
relevant for human T1D and use of scRNA-seq analysis to uncover critical clues about shared
transcriptional programs related to the pathogenic potential between human and mouse HP reactive
T cells. Completion of this project could lead to better biomarkers to predict T1D risk and disease
progression.
总结
1型糖尿病(T1 D)是一种自身免疫性疾病,
由T细胞介导的胰岛β细胞破坏引起的耐受性。糖尿病是由HLAII-
通过与B细胞和CD 8 + T细胞的细胞相互作用,
自身抗体产生和β细胞死亡。虽然抗胰岛自身抗体目前
作为T1 D发展的最佳预测因子,筛查仅限于四种胰岛抗原,
生物标志物存在。尽管多年的研究,仍然不清楚哪些抗原特异性CD 4 + T细胞
启动T1 D新的证据表明,胰岛β细胞融合形成的杂合肽(HP
蛋白质可能是T1 D中的关键抗原,因为最近的研究发现HP反应性CD 4 + T细胞来自
T1 D患者和糖尿病小鼠体外。这些新抗原逃避了中枢耐受,
由外周机制控制,包括无反应性或调节性T细胞控制。初步
研究中,我们使用四聚体试剂鉴定了糖尿病小鼠模型中的HP特异性CD 4 + T细胞,
并表明它们是致病性的,并在小鼠转移模型中引起T1 D。更重要的是我们可以
当存在时,靶向一种杂合肽阻断NOD小鼠模型中自发的T1 D
使用肽特异性MHCII阻断抗体的小鼠MHCII。因此,我们假设HP是
关键抗原和对HP的自身反应性启动T1 D。本提案的目标是
确定HP特异性CD 4 + T细胞是否启动T1 D,以及靶向它们是否可以导致耐受,
预防或治疗T1 D。该基金的第二个目标是确定HP特异性细胞是否
与人类T1 D相关,并使用scRNA-seq分析来揭示共享的关键线索。
与人类和小鼠HP反应性之间致病潜力相关的转录程序
T细胞。该项目的完成可能会导致更好的生物标志物来预测T1 D风险和疾病
进展
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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Brian T Fife其他文献
Brian T Fife的其他文献
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{{ truncateString('Brian T Fife', 18)}}的其他基金
Identifying and preventing antigen specific T cells in diabetes
识别和预防糖尿病中的抗原特异性 T 细胞
- 批准号:
10436364 - 财政年份:2021
- 资助金额:
$ 59.03万 - 项目类别:
Identifying and preventing antigen specific T cells in diabetes
识别和预防糖尿病中的抗原特异性 T 细胞
- 批准号:
10296946 - 财政年份:2021
- 资助金额:
$ 59.03万 - 项目类别:
Engineering CAR Tregs for type 1 diabetes
工程 CAR Tregs 治疗 1 型糖尿病
- 批准号:
10495238 - 财政年份:2021
- 资助金额:
$ 59.03万 - 项目类别:
Engineering CAR Tregs for type 1 diabetes
工程 CAR Tregs 治疗 1 型糖尿病
- 批准号:
10354415 - 财政年份:2021
- 资助金额:
$ 59.03万 - 项目类别:
Multiplex immune analysis of antigen specific CD4+ T cells in autoimmune diabetes
自身免疫性糖尿病中抗原特异性 CD4 T 细胞的多重免疫分析
- 批准号:
9091431 - 财政年份:2015
- 资助金额:
$ 59.03万 - 项目类别:
Multiplex immune analysis of antigen specific CD4+ T cells in autoimmune diabetes
自身免疫性糖尿病中抗原特异性 CD4 T 细胞的多重免疫分析
- 批准号:
9271151 - 财政年份:2015
- 资助金额:
$ 59.03万 - 项目类别:
Multiplex immune analysis of antigen specific CD4+ T cells in autoimmune diabetes
自身免疫性糖尿病中抗原特异性 CD4 T 细胞的多重免疫分析
- 批准号:
8932879 - 财政年份:2015
- 资助金额:
$ 59.03万 - 项目类别:
Mechanisms of immune tolerance in autoimmune diabetes
自身免疫性糖尿病的免疫耐受机制
- 批准号:
8786472 - 财政年份:2013
- 资助金额:
$ 59.03万 - 项目类别:
Mechanisms of immune tolerance in autoimmune diabetes
自身免疫性糖尿病的免疫耐受机制
- 批准号:
8649238 - 财政年份:2013
- 资助金额:
$ 59.03万 - 项目类别:
Mechanisms of immune tolerance in autoimmune diabetes
自身免疫性糖尿病的免疫耐受机制
- 批准号:
9181377 - 财政年份:2013
- 资助金额:
$ 59.03万 - 项目类别:
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