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.
摘要 1型糖尿病(T1D)的特征是由于自身免疫事件而无法达到正常血糖 错误地破坏了胰腺中产生胰岛素的β细胞。T1D的主要挑战是 慢性自身免疫破坏β细胞和(2)恢复是不可逆转的两重打击 由于反复的慢性自身反应性攻击而丢失。尽管目前的治疗方法确实温和地减少了 高血糖,它们可能无意中导致严重的健康并发症(即全身性免疫抑制 药物损害自然宿主免疫,放松对生理功能的调节,异体移植得到满足 有急性/慢性排斥反应)。该实验室的长期目标是直接应对这些挑战 通过发展抗原特异性耐受抑制自身免疫介导的事件有效缓解T1D 再加上胰岛素恢复策略,以缓解高血糖。这些调查有两个主要方面 旨在应对这一挑战:(1)设计MHC II类修饰的致耐受树突状细胞免疫疗法 在不损害自然宿主的情况下,专门抑制β细胞间的自身反应性攻击 免疫(对病原体或转化的细胞),以及(2)供体来源的MHC I类相合的发展 在新的生物材料中种植β细胞,以恢复胰岛素的产生和正常的血糖水平。为 第一个目标, 研究将通过敲除负责的关键基因来将DC重新编程为耐受状态 管辖豁免权。该方法与沉默内源性MHC II类并取代 带有编码修饰的MHC II类的转基因,该修饰的MHC II类仅提供β细胞自身抗原肽 亲和力很强。结果将导致耐受性DC仅呈现MHC II类限制性β细胞 体内过继转移时的自身抗原,导致抑制自身反应性T细胞反应 损害正常的宿主适应性免疫。即使成功阻止了反复的自体反应性T细胞攻击, 组织损伤在T1D的中晚期往往是不可逆的。为了应对这一挑战,第二个目标 将开发一种恢复性方法,使用供体来源的MHC I类匹配的贝塔细胞种植在新的 恢复体内胰岛素产生的生物材料。捐赠者来源的贝塔细胞将被基因重新编程以 与受者的单倍型匹配的Express MHC I类;该方法将突出供体的使用价值 恢复性使用的纸巾。这些产生胰岛素的供体来源的MHC I类匹配的β细胞将 然后在植入非肥胖糖尿病小鼠模型之前种植一种新的专利生物材料。 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的进展。 依赖胰岛素的产生。这些研究产生的结果将支持创新的发展 和新的翻译和临床相关的治疗应用,以对抗T1D。

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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