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

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.
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项目成果

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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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Autoantibodies directed to islet cell surface antigens and their pathologic roles in type-1 diabetes
针对胰岛细胞表面抗原的自身抗体及其在 1 型糖尿病中的病理作用
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肿瘤相关抗原的自身抗体作为肝脏的诊断生物标志物可以
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Autoantibodies to tumor-associated antigens as diagnostic biomarkers in liver can
肿瘤相关抗原的自身抗体作为肝脏的诊断生物标志物可以
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    8704893
  • 财政年份:
    2011
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Autoantibodies to tumor-associated antigens as diagnostic biomarkers in liver can
肿瘤相关抗原的自身抗体作为肝脏的诊断生物标志物可以
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Autoantibodies to tumor-associated antigens as diagnostic biomarkers in liver can
肿瘤相关抗原的自身抗体作为肝脏的诊断生物标志物可以
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滤泡排除自身抗原可防止自身抗体的产生
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Follicular Exclusion of Self Antigens Prevents Development of Autoantibodies
滤泡排除自身抗原可防止自身抗体的产生
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通过自身抗体组学鉴定 NHL 患者血浆中与自身抗体结合的非霍奇金淋巴瘤 (NHL) 特异性抗原
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  • 资助金额:
    $ 59.03万
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