Development of tolerogenic dendritic cell-based immunotherapies and restorative insulin approaches to alleviate type 1 diabetes

开发基于耐受性树突状细胞的免疫疗法和恢复性胰岛素方法以缓解 1 型糖尿病

基本信息

  • 批准号:
    10189649
  • 负责人:
  • 金额:
    $ 37.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-07-01 至 2022-04-30
  • 项目状态:
    已结题

项目摘要

SUMMARY Type 1 diabetes (T1D) is characterized by an inability to achieve normoglycemia due to autoimmune events mistakenly targeting destruction of insulin-producing beta-cells of the pancreas. The major challenge of T1D is the two-fold onslaught whereby (1) chronic autoimmunity destroys beta-cells and (2) recovery is irreversibly lost due to the repeated chronic autoreactive attacks. Although current treatments do temperately reduce hyperglycemia, they can inadvertently lead to significant health complications (i.e. global immunosuppressive drugs impair natural host immunity and deregulate physiological functions and allogenic transplants are met with acute/chronic rejection). The long-term goals of the laboratory are to directly address these challenges of effectively alleviating T1D by developing antigen-specific tolerance to restrain autoimmune-mediated events coupled with insulin restorative strategies to alleviate hyperglycemia. The investigations have two principal aims to tackle this challenge: (1) engineering MHC class II-modified tolerogenic dendritic cell immunotherapies to specifically restrain autoreactive attacks in the beta-cell compartment without impairing natural host immunity (to pathogens or transformed cells), and (2) development of donor-derived MHC class I-matched beta-cells seeded in novel biomaterials to restore insulin production and normalize blood glucose levels. For the first aim, studies will reprogram DC towards tolerogenic states by knocking out key genes responsible for governing immunity. The approach is combined with silencing of endogenous MHC class II and replacing that with a transgene encoding a modified MHC class II that exclusively presents beta-cell autoantigen peptides with high affinity. Results will lead to tolerogenic DC solely presenting MHC class II-restricted beta-cell autoantigens upon adoptive transfer in vivo, leading to restrained autoreactive T cell responses without impairing normal host adaptive immunity. Even with success in stopping repeated autoreactive T cell attacks, tissue damage is often irreversible in mid- and late-stages of T1D. To address this challenge, the second aim will develop a restorative approach using donor-derived MHC class I-matched beta-cells seeded on novel biomaterials to restore insulin production in vivo. Donor-derived beta-cells will be genetically reprogrammed to express MHC class I matched to the recipient's haplotype; the approach will highlight the value in use of donor tissues for restorative applications. These insulin-producing donor-derived MHC class I-matched beta-cells will then be seeded in a novel patented biomaterial prior to implantation in the non-obese diabetic mouse model. Success of the approach will restrain diabetes progression by restoring normoglycemia through glucose- dependent insulin production. Findings generated from these studies will support development of innovative and novel translational and clinical-relevant therapeutic applications for combating T1D.
概括 1型糖尿病(T1D)的特征是由于自身免疫事件无法实现正常血糖 错误地针对胰腺产生胰岛素的β细胞的破坏。 T1D的主要挑战是 (1)慢性自动免疫破坏了β细胞,(2)恢复是不可逆转的 由于反复的慢性自动反应性攻击而损失。尽管目前的治疗确实会降低 高血糖,它们可以无意中导致重大的健康并发症(即全球免疫抑制作用 药物会损害天然宿主免疫力和放松管制的生理功能和同种异体移植物 急性/慢性排斥)。实验室的长期目标是直接应对这些挑战 通过开发抗原特异性耐受性来有效地减轻T1D,以限制自身免疫介导的事件 再加上胰岛素修复策略,以减轻高血糖。调查有两名校长 旨在应对这一挑战:(1)工程MHC II类改性的耐受性树突状细胞免疫疗法 特别限制β细胞隔间中的自动反应性攻击,而不会损害天然宿主 免疫力(对病原体或转化的细胞),以及(2)供体衍生的MHC I类匹配的开发 β细胞播种在新型生物材料中,以恢复胰岛素的产生并使血糖水平归一化。为了 第一个目标, 研究将通过淘汰负责的关键基因来对DC进行重编程DC。 管理免疫。该方法与内源性MHC II类沉默相结合,并取代 使用的转基因编码改良的MHC II类,该类别仅显示β细胞自动抗原肽 具有高亲和力。结果将导致耐受性直流仅显示MHC II类限制性β细胞 自动抗原在体内收养时,导致自动反应性T细胞反应受到约束 损害正常宿主自适应免疫。即使成功停止重复自动反应性T细胞攻击, 在T1D的中期和晚期,组织损伤通常是不可逆的。为了应对这一挑战,第二个目标 将使用播种在新颖的供体的I类匹配的Beta细胞中开发一种恢复性方法 生物材料在体内恢复胰岛素的产生。供体衍生的Beta细胞将在基因上重新编程为 Express MHC I类与收件人的单倍型匹配;该方法将突出捐助者使用的价值 用于恢复应用的组织。这些产生胰岛素的供体衍生的MHC I类匹配的Beta细胞将 然后在非肥胖糖尿病小鼠模型中植入之前将新型的专利生物材料播种。 该方法的成功将通过通过葡萄糖恢复正常血糖来抑制糖尿病进展 依赖性胰岛素的产生。这些研究产生的发现将支持创新的发展 以及对抗T1D的新型翻译和临床治疗应用。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Antimony resistance associated with persistence of Leishmania (Leishmania) infantum infection in macrophages.
锑抗性与巨噬细胞中婴儿利什曼原虫(Leishmania)感染的持续存在相关。
  • DOI:
    10.1007/s00436-021-07231-7
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    2
  • 作者:
    Magalhães,LucasSousa;Bomfim,LaysGiseleSantos;Santos,CamillaNatáliaOliveira;DosSantos,PriscilaLima;Tanajura,DiegoMoura;Lipscomb,MichaelWheeler;deJesus,AméliaRibeiro;deAlmeida,RoquePacheco;deMoura,TatianaRodrigues
  • 通讯作者:
    deMoura,TatianaRodrigues
Leishmania donovani infection suppresses Allograft Inflammatory Factor-1 in monocytes and macrophages to inhibit inflammatory responses.
  • DOI:
    10.1038/s41598-020-79068-6
  • 发表时间:
    2021-01-13
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    da Silva RL;Elizondo DM;Brandy NZD;Haddock NL;Boddie TA;de Oliveira LL;de Jesus AR;de Almeida RP;de Moura TR;Lipscomb MW
  • 通讯作者:
    Lipscomb MW
Space-time risk cluster of visceral leishmaniasis in Brazilian endemic region with high social vulnerability: An ecological time series study.
  • DOI:
    10.1371/journal.pntd.0009006
  • 发表时间:
    2021-01
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    Ribeiro CJN;Dos Santos AD;Lima SVMA;da Silva ER;Ribeiro BVS;Duque AM;Peixoto MVS;Dos Santos PL;de Oliveira IM;Lipscomb MW;de Araújo KCGM;de Moura TR
  • 通讯作者:
    de Moura TR
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Michael W Lipscomb其他文献

Michael W Lipscomb的其他文献

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{{ truncateString('Michael W Lipscomb', 18)}}的其他基金

Deciphering the immunoregulatory network governing antigen presenting myeloid cells
破译控制抗原呈递骨髓细胞的免疫调节网络
  • 批准号:
    10629283
  • 财政年份:
    2022
  • 资助金额:
    $ 37.75万
  • 项目类别:
Delineating the function of MHC class III genes in antigen presenting myeloid cell contribution to autoimmunity
描述 MHC III 类基因在抗原呈递骨髓细胞对自身免疫的贡献中的功能
  • 批准号:
    10429530
  • 财政年份:
    2022
  • 资助金额:
    $ 37.75万
  • 项目类别:
Delineating the function of MHC class III genes in antigen presenting myeloid cell contribution to autoimmunity
描述 MHC III 类基因在抗原呈递骨髓细胞对自身免疫的贡献中的功能
  • 批准号:
    10641866
  • 财政年份:
    2022
  • 资助金额:
    $ 37.75万
  • 项目类别:
Deciphering the immunoregulatory network governing antigen presenting myeloid cells
破译控制抗原呈递骨髓细胞的免疫调节网络
  • 批准号:
    10792697
  • 财政年份:
    2022
  • 资助金额:
    $ 37.75万
  • 项目类别:
Deciphering the immunoregulatory network governing antigen presenting myeloid cells
破译控制抗原呈递骨髓细胞的免疫调节网络
  • 批准号:
    10405313
  • 财政年份:
    2022
  • 资助金额:
    $ 37.75万
  • 项目类别:
Crosstalk and the cytoskeleton in dendritic cell antigen presentation
树突状细胞抗原呈递中的串扰和细胞骨架
  • 批准号:
    8795050
  • 财政年份:
    2015
  • 资助金额:
    $ 37.75万
  • 项目类别:

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