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Precise targeting of T1D specific T cells using CAR and peptide-MHC chimeric antigen ligands

Precise targeting of T1D specific T cells using CAR and peptide-MHC chimeric antigen ligands
使用 CAR 和肽-MHC 嵌合抗原配体精确靶向 T1D 特异性 T 细胞
批准号:
10621960
负责人:
Michael Birnbaum
金额:
$67.46万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-05-15 至 2026-04-30

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中文摘要
翻译
项目摘要 1型糖尿病(T1 D)是一种无法治愈的自身免疫性疾病,表现为胰岛细胞的免疫破坏, β细胞该提案描述了一种独特的CAR T细胞方法来消除胰岛自身反应性T细胞, 消除了自身免疫的来源,并为T1 D提供了高度特异性的治疗。我们将利用 我们最近开发的具有嵌合抗原配体(CAL)衔接子的分裂CAR系统由pMHC 多聚体与募集分子融合。CAL的添加将结合自身反应性TCR并募集免疫应答。 通用CAR T细胞杀死自身反应性T1 D特异性T细胞。这些实验将检验假设- (1)我们的模块化CAR/CAL系统是唯一适合专门针对多个汽车, 反应性TCR,以及(2)我们可以鉴定针对T1 D特异性TCR的新表位,以与 CAR/CAL系统。重要的是,初步的数据支持这些假设, T1 D患者的标本和严格的实验设计建立在这个建议与基本的 跨学科合作和专业知识,包括合成生物学,大规模表位发现, T1 D免疫学和人源化T1 D动物建模。这一五年计划的具体目标是: 目的1建立并优化针对抗原特异性人TCR的CAL体系,目的2表征 来自T1 D患者/供体的TCR的自身反应性和鉴定针对这些TCR的肽-MHC,以及Aim 3 评价CAL系统在人源化T1 D动物模型中的性能。这项工作的成果将 确立CAR/CAL系统作为安全、有效和潜在治愈性T1 D治疗的临床潜力。
英文摘要
Project Summary Type 1 diabetes (T1D) is an incurable autoimmune disease manifested through the immune destruction of islet beta cells. This proposal describes a unique CAR T cell approach to eliminate islet-autoreactive T cells, thus eliminating the source of the autoimmunity and providing a highly specific treatment for T1D. We will leverage our recently developed split CAR system with a chimeric antigen ligand (CAL) adaptor consisting of a pMHC multimer fused to a recruitment molecule. The addition of CAL will bind to the autoreactive TCR and recruit the universal CAR T cells to kill autoreactive T1D specific T cells. The proposed experiments will test the hypoth- eses that (1) our modular CAR/CAL systems are uniquely suited for specifically targeting multiple auto- reactive TCRs, and (2) that we can identify novel epitopes against T1D specific TCRs to be paired with the CAR/CAL system. Importantly, preliminary data support these hypotheses, and well-characterized clinical specimens from T1D patients and rigorous experimental designs are established in this proposal with essential cross-disciplinary collaborations and expertise that encompass synthetic biology, large-scale epitope discovery, T1D immunology, and humanized T1D animal modeling. The specific aims of this five-year proposal are as follows: Aim 1 establish and optimize the CAL system against antigen-specific human TCRs, Aim 2 characterize the autoreactivity of TCRs from T1D patients/donors and identify peptide-MHC against these TCRs, and Aim 3 evaluate the performance of the CAL system in humanized T1D animal models. Outcomes from this work will establish the clinical potential of the CAR/CAL system as a safe, effective, and potentially curative T1D treatment.
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Precise targeting of T1D specific T cells using CAR and peptide-MHC chimeric antigen ligands
Development of an emulsion-based method for repertoire-scale paired-chain T cell receptor sequencing
Repertoire-scale T cell antigen identification via peptide-MHC lentivirus display
Determining antigen recognition in systemic sclerosis
  • 批准号:
    10188400
  • 项目类别:
  • 资助金额:
    $4.3万
  • 财政年份:
    2014
  • 负责人:
    Michael Birnbaum
  • 依托单位:
海外基金