Parameters T-Cell Receptor avidity during thymic selection in autoimmune diabetes

参数 自身免疫性糖尿病胸腺选择过程中 T 细胞受体亲合力

基本信息

  • 批准号:
    8635533
  • 负责人:
  • 金额:
    $ 16.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-08-01 至 2016-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Type I Diabetes (T1D) or juvenile diabetes, is an early onset autoimmune disease that culminates in the targeting and destruction of ¿ cells found within the pancreatic islets of Langerhans. Little is known about how autoreactive lymphocytes escape negative selection in the thymus, resulting in the breakdown in central tolerance. Understanding the mechanisms of autoimmune T cell selection and development is crucial for identifying the underlying issues in the breakdown in central tolerance and may be applicable in establishing peripheral tolerance to islet antigen specific autoimmune T cells. Due to the low clonal frequency of autoreactive T cells in the thymus and periphery, studies into underlying mechanisms in self-reactive T cell selection and survival have been challenging. To bypass this issue, T cell receptor (TCR) transgenic models have been utilized, however only a limited number of islet antigen specific TCR transgenic models have been described [1-4]. Therefore, there has been limited study into the mechanisms of autoreactive TCR selection in the thymus, and most of the knowledge we have about the role of negative selection in limiting self-reactivity is based on studies done with model antigens, not with TCRs obtained during an autoimmune response. To address this issue, we have composed a panel of ten insulin specific TCRs with variable reactivity to insulin, the majority of which have been isolated from the islets of spontaneously diabetic non-obese diabetic (NOD) mice. Insulin has been shown to be a major antigen in development of autoimmune diabetes on the NOD background, and antibodies to insulin are used as predictive biomarkers in human disease. In this proposal we plan to study the development of these T cell clones in the thymus through the use of a new approach for the rapid generation of TCR transgenic mice, called retrogenic mice, using retroviral-mediated stem cells gene transfer and novel 'self-cleaving' 2A peptide-linked multicistronic retroviral vectors that express both TCR chains in a single vector [5-14]. This will allow us to quickly generate a large number of TCR retrogenic mice with ten different TCR's to study the fate of a single TCR during positive and negative selection. We will be able to elucidate the role of thymically expressed insulin in central tolerance by utilizing mice with reduced thymic expression of insulin and mice with mutated insulin TCR contact residue. In addition, we want to establish whether insulin reactive TCR's can be deleted in the thymus using DEC-205 insulin and insulin mimetope fusion peptide antibodies. Finally, we propose to express insulin in an inducible manner, under the Aire promoter, in an effort to establish central tolerance. We hypothesize that our unique panel of insulin reactive TCRs can be used to define the threshold for positive and negative selection of autoreactive insulin specific thymocytes.
描述(由申请人提供):I型糖尿病(T1 D)或青少年糖尿病,是一种早期发病的自身免疫性疾病,其最终导致胰岛内发现的细胞的靶向和破坏。关于自身反应性淋巴细胞如何逃避胸腺中的负选择,导致中枢耐受性的破坏,我们知之甚少。了解自身免疫性T细胞选择和发育的机制对于确定中枢耐受性破坏的潜在问题至关重要,并且可能适用于建立对胰岛抗原特异性自身免疫性T细胞的外周耐受性。由于胸腺和外周中自身反应性T细胞的克隆频率低,对自身反应性T细胞选择和存活的潜在机制的研究一直具有挑战性。为了绕过这个问题,已经利用了T细胞受体(TCR)转基因模型,然而仅描述了有限数量的胰岛抗原特异性TCR转基因模型[1-4]。因此,对胸腺中自身反应性TCR选择机制的研究有限,我们对负选择在限制自身反应性中的作用的大部分知识都是基于对模型抗原的研究,而不是对自身免疫反应期间获得的TCR的研究。为了解决这个问题,我们已经组成了一组10个胰岛素特异性TCR与胰岛素的可变反应性,其中大部分已被分离的胰岛自发性糖尿病非肥胖糖尿病(NOD)小鼠。胰岛素已被证明是NOD背景下自身免疫性糖尿病发展的主要抗原,胰岛素抗体被用作人类疾病的预测生物标志物。在该提案中,我们计划通过使用逆转录病毒介导的干细胞基因转移和在单个载体中表达两条TCR链的新型“自切割”2A肽连接多顺反子逆转录病毒载体,使用快速生成TCR转基因小鼠(称为逆转录小鼠)的新方法研究胸腺中这些T细胞克隆的发育[5-14]。这将使我们能够快速产生大量具有十种不同TCR的TCR逆转录小鼠,以研究单个TCR在阳性和阴性选择过程中的命运。我们将能够阐明胸腺表达的胰岛素在中枢耐受性中的作用,通过利用胸腺胰岛素表达减少的小鼠和具有突变的胰岛素TCR接触残基的小鼠。此外,我们想确定是否可以使用DEC-205胰岛素和胰岛素受体融合肽抗体在胸腺中删除胰岛素反应性TCR。最后,我们建议在Aire启动子下以诱导方式表达胰岛素,以建立中枢耐受性。我们假设我们独特的胰岛素反应性TCR组可用于定义自身反应性胰岛素特异性胸腺细胞的阳性和阴性选择的阈值。

项目成果

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Matthew Bettini其他文献

Matthew Bettini的其他文献

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{{ truncateString('Matthew Bettini', 18)}}的其他基金

Early life regulation of microbiota specific thymic T cell development
微生物群特异性胸腺 T 细胞发育的早期生命调节
  • 批准号:
    10568756
  • 财政年份:
    2022
  • 资助金额:
    $ 16.2万
  • 项目类别:
Self-Reactive T Cell Development in Type 1 Diabetes
1 型糖尿病中的自身反应性 T 细胞发育
  • 批准号:
    10413081
  • 财政年份:
    2019
  • 资助金额:
    $ 16.2万
  • 项目类别:
Self-Reactive T Cell Development in Type 1 Diabetes
1 型糖尿病中的自身反应性 T 细胞发育
  • 批准号:
    10026565
  • 财政年份:
    2019
  • 资助金额:
    $ 16.2万
  • 项目类别:
Microbiota Specific T Cell Selection
微生物群特异性 T 细胞选择
  • 批准号:
    10308400
  • 财政年份:
    2018
  • 资助金额:
    $ 16.2万
  • 项目类别:
Microbiota Specific T Cell Selection
微生物群特异性 T 细胞选择
  • 批准号:
    10532220
  • 财政年份:
    2018
  • 资助金额:
    $ 16.2万
  • 项目类别:
Parameters T-Cell Receptor avidity during thymic selection in autoimmune diabetes
参数 自身免疫性糖尿病胸腺选择过程中 T 细胞受体亲合力
  • 批准号:
    8900917
  • 财政年份:
    2014
  • 资助金额:
    $ 16.2万
  • 项目类别:

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