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Identifying and preventing antigen specific T cells in diabetes

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
负责人:
Brian T Fife
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
项目状态:
未结题
起止时间:
2021-06-22 至 2026-05-31

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中文摘要
翻译
摘要 1型糖尿病(T1D)是一种自身免疫性疾病,由免疫学崩溃引起 T细胞介导的胰岛β细胞破坏引起的耐受。糖尿病是由HLAII策划的- 限制CD4+T细胞,通过与B细胞和CD8+T细胞的细胞相互作用,导致 自身抗体的产生和β细胞的死亡。而抗胰岛自身抗体目前 T1D发生的最佳预测因子,筛查仅限于四种胰岛抗原和无T细胞 生物标志物是存在的。尽管进行了多年的研究,但目前仍不清楚哪些抗原特异性的CD4+T细胞 启动T1D。新证据表明,杂交肽(HP)是由胰岛β细胞融合形成的 蛋白质可能是T1D的关键抗原,因为最近的研究发现,Hp反应的CD4+T细胞来自 T1D患者和糖尿病小鼠的体外实验。这些新抗原逃脱了中枢耐受,必须是 由外周机制控制,包括无能或调节性T细胞控制。在预赛中 研究中,我们使用四聚体试剂在糖尿病小鼠模型中鉴定了Hp特异性的CD4+T细胞, 并在小鼠转移模型中证明它们是致病的并引起T1D。更重要的是,我们可以 在NOD小鼠模型中阻断以一种杂交肽为靶点的自发T1D 小鼠MHCII使用多肽特异性:MHCII封闭抗体。因此,我们假设HPS是 关键抗原和对HPS的自身反应性启动T1D。这项提议的目标是 确定幽门螺杆菌特异性的CD4+T细胞是否启动T1D,以及靶向它们是否会导致耐受性 预防或治疗T1D。这项资助的第二个目标是确定幽门螺杆菌特异性细胞是否 与人类T1D相关,并使用scRNA-seq分析来发现有关共享的关键线索 与人和小鼠幽门螺杆菌致病潜能相关的转录程序 T细胞。该项目的完成可能会带来更好的生物标志物来预测T1D风险和疾病 进步。
英文摘要
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.
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Identifying and preventing antigen specific T cells in diabetes
  • 批准号:
    10634700
  • 项目类别:
  • 资助金额:
    $59.03万
  • 财政年份:
    2021
  • 负责人:
    Brian T Fife
  • 依托单位:
Identifying and preventing antigen specific T cells in diabetes
  • 批准号:
    10296946
  • 项目类别:
  • 资助金额:
    $59.0万
  • 财政年份:
    2021
  • 负责人:
    Brian T Fife
  • 依托单位:
Engineering CAR Tregs for type 1 diabetes
  • 批准号:
    10495238
  • 项目类别:
  • 资助金额:
    $23.15万
  • 财政年份:
    2021
  • 负责人:
    Brian T Fife
  • 依托单位:
Engineering CAR Tregs for type 1 diabetes
  • 批准号:
    10354415
  • 项目类别:
  • 资助金额:
    $19.28万
  • 财政年份:
    2021
  • 负责人:
    Brian T Fife
  • 依托单位:
国内基金
海外基金
Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
  • 批准号:
    2022J011295
  • 项目类别:
    省市级项目
  • 资助金额:
    10.0万元
  • 批准年份:
    2022
  • 负责人:
    王亚伟
  • 依托单位:
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究