Designer Tregs for restoring tolerance in patients with type 1 diabetes

用于恢复 1 型糖尿病患者耐受性的设计 Tregs

基本信息

项目摘要

ABSTRACT In type I diabetes, pancreatic islets are destroyed by an autoimmune reaction. Thus, a general strategic goal for preventing islet loss is to locally suppress this autoimmune response, while avoiding systemic immune suppression. FoxP3-expressing T regulatory cells (Tregs) are immune cells that play a central role in local tolerance, and therefore could serve as a potential platform for a cell therapy to prevent islet loss. Tregs have many attractive attributes as a suppressive cell therapy: they can exert dominant immunosuppressive actions, through cell-cell interactions or production of suppressive cytokines; they can in principle be long lived; and tolerance induced by Tregs can persist through infectious tolerance by conferring tolerogenic properties to neighboring cells. In mouse models, single infusion of Tregs can prevent and reverse diabetes indefinitely. The encouraging preliminary data in mouse models have let to the development of ongoing clinical trials of Treg cell therapies in humans. Nonetheless, Treg cell therapy presents several key challenges: it is hard to specifically target them to the islets and avoid systemic suppression, they are hard to expand in sufficient numbers (especially relative to conventional effector T cells), and their cell fate can be changed, especially in particular inflammatory microenvironments. In the past few years, however, there have been remarkable advances in using conventional T cells for cancer therapy (e.g. CAR T cells), including an explosion of new synthetic biology tools that can be used to precisely target T cells to disease tissues, to control their fate and proliferation, and to even give them the capability to locally deliver non-natural therapeutic payloads. Here our goal is to bring these new tools to bear on the problem of engineering improved islet-specific therapeutic suppressive cells. Our aims are to: 1) engineer natural Tregs with improved targeting and recognition of islets 2) develop tools to selectively expand therapeutic Tregs in vivo and enhance their stability 3) design synthetic suppressor cells that disarm effectors, dampen inflammation and promote islet repair These approaches wed cutting-edge synthetic biology with multiple strategies for developing therapeutic suppressor cells. We will establish proof-of-concept data using mouse model of autoimmune diabetes and apply them to test engineered human Tregs targeted to human islets using a humanized mouse model of autoimmune islet inflammation. Successful completion of this study will provide preclinical data for future implementation of these strategies in clinical trials.
摘要

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Next-generation regulatory T cell therapy.
  • DOI:
    10.1038/s41573-019-0041-4
  • 发表时间:
    2019-10
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ferreira LMR;Muller YD;Bluestone JA;Tang Q
  • 通讯作者:
    Tang Q
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JEFFREY A BLUESTONE其他文献

JEFFREY A BLUESTONE的其他文献

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{{ truncateString('JEFFREY A BLUESTONE', 18)}}的其他基金

Project 2 - Specificity and repertoire of Tregs in T1D
项目 2 - T1D 中 Tregs 的特异性和全部功能
  • 批准号:
    9151389
  • 财政年份:
    2016
  • 资助金额:
    $ 335.17万
  • 项目类别:
Donor-Alloantigen-Reactive Regulatory T Cell Therapy in Liver Transplantation
肝移植中供体同种异体抗原反应性调节性 T 细胞治疗
  • 批准号:
    8672260
  • 财政年份:
    2014
  • 资助金额:
    $ 335.17万
  • 项目类别:
Role of Innate Lymphoid Cells in Autoimmunity
先天淋巴细胞在自身免疫中的作用
  • 批准号:
    8637675
  • 财政年份:
    2013
  • 资助金额:
    $ 335.17万
  • 项目类别:
"Donor-Specific Regulatory T Cell Therapy in Liver Transplantation"
“肝移植中供体特异性调节性 T 细胞治疗”
  • 批准号:
    8728396
  • 财政年份:
    2012
  • 资助金额:
    $ 335.17万
  • 项目类别:
"Donor-Specific Regulatory T Cell Therapy in Liver Transplantation"
“肝移植中供体特异性调节性 T 细胞治疗”
  • 批准号:
    8264452
  • 财政年份:
    2012
  • 资助金额:
    $ 335.17万
  • 项目类别:
Spontaneous Autoimmune Model of Peripheral Neuropathy
周围神经病变的自发性自身免疫模型
  • 批准号:
    8116742
  • 财政年份:
    2010
  • 资助金额:
    $ 335.17万
  • 项目类别:
"Expanding beta-cell mass"
“扩大β细胞量”
  • 批准号:
    7994038
  • 财政年份:
    2010
  • 资助金额:
    $ 335.17万
  • 项目类别:
"Expanding beta-cell mass"
“扩大β细胞量”
  • 批准号:
    8322756
  • 财政年份:
    2010
  • 资助金额:
    $ 335.17万
  • 项目类别:
"Expanding beta-cell mass"
“扩大β细胞量”
  • 批准号:
    8143503
  • 财政年份:
    2010
  • 资助金额:
    $ 335.17万
  • 项目类别:
Genetically Engineered Antigen Specific Treg to Treat Autoimmunity
基因工程抗原特异性 Treg 治疗自身免疫性疾病
  • 批准号:
    7688822
  • 财政年份:
    2009
  • 资助金额:
    $ 335.17万
  • 项目类别:

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精氨酸转运对胰腺α细胞增殖和功能的作用
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    2022
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精氨酸调节α细胞增殖和功能
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靶向 α 细胞 GPCR 刺激胰高血糖素并对抗低血糖
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使用精密切割的胰腺切片结合高时空显微镜阐明人类 1 型糖尿病的 α 细胞缺陷
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定义 2 型糖尿病治疗的 α 细胞胰高血糖素原加工过程
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