Antigen-specific tolerance in T1 diabetes by IDO loaded functionalized dendrimers

IDO 负载功能化树枝状聚合物对 T1 糖尿病的抗原特异性耐受

基本信息

  • 批准号:
    8488094
  • 负责人:
  • 金额:
    $ 18.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-09-04 至 2015-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Induction of antigen-specific tolerance is perceived as the Holy Grail for the treatment of T1D, either early after onset or following islet transplantatio. Although the list of auto-antigens in T1D is far from being complete, and it is still unknown which one (if any) is the most "important" one, accumulating evidence suggests that insulin is a key target of pathogenic T cells in type 1 diabetes in both NOD mice and humans, and that it may even be the long-sought-after 'initiating antigen' in this disease. Given the important role of dendritic cells (DCs) in the establishment of peripheral T cell tolerance, DC-based strategies are being explored as an important route to promote tolerance. In fact, advancements in the understanding of fetal-maternal and of tumor-induced tolerance highlight the key role that tolerogenic DC expressing Indoleamine-2,3 Dioxygenase (IDO) play in this process. Moreover, in vitro transfection of DC shows that IDO is sufficient to induce a tolerogenic phenotype. Current DC-based protocols aimed at the induction of tolerance require the in vitro preparation and transfection of autologous DC before reinfusion into patients. As such, the cost and technical challenges of the procedure appear overwhelming and require highly specialized centers. To overcome this limit, we propose the use of a novel nanostructure gene-based vaccine delivery that efficiently and specifically targets antigen-presenting cells (APC). Our strategy is therefore based on the selective targeting of DCs to co-deliver, as DNA, a disease-relevant autoantigen together with IDO in vivo using our nano-platform. We expect that, following targeted DNA transfection, the simultaneous expression of insulin and IDO by DC will induce a tolerogenic response that will mitigate/halt autoimmune destruction of islets. This platform is based on polyamidoamine (PAMAM) dendrimer (as a DNA loading surface) covalently conjugated to an MHC class II binding peptide that acts as a ligand to target APC, in particular DCs. The platform will be tested in NOD mice by evaluating: 1) its capacity to induce tolerance in adoptively transferred insulin-specific T cells and 2) its therapeutic efficacy in prevention of or at diabetes onset. The proposed peptide-dendrimer platform for in vivo targeted gene delivery should result in the same (or even a higher) tolerogenic efficacy seen with traditional methods for APC preparation, with sizable advantages including: i) low cost (one dose of peptide-dendrimer is estimated to cost 1$), and ii) simplicity in preparation and administration reducing the need for specialized center. Moreover, by using the INS B9-B29 targeting peptide that binds with high affinity not only the IAg7 MHC class II molecule, but also the human HLA DQ8 molecule, this platform opens the realistic possibility of an easy translation of positive findings towards the clinic.
描述(由申请人提供):诱导抗原特异性耐受被认为是治疗 T1D 的圣杯,无论是在发病后早期还是在胰岛移植后。尽管 T1D 自身抗原清单还远未完成,目前仍不清楚是哪些 其中一项(如果有的话)是最“重要”的一项,越来越多的证据表明,胰岛素是 NOD 小鼠和人类 1 型糖尿病致病性 T 细胞的关键靶标,甚至可能是人们长期追捧的“这种疾病中的“起始抗原”。鉴于树突状细胞 (DC) 在建立外周 T 细胞耐受中的重要作用,基于 DC 的策略正在被探索作为促进耐受的重要途径。事实上,对胎儿母体耐受性和肿瘤诱导耐受性理解的进步凸显了表达吲哚胺-2,3双加氧酶 (IDO) 的耐受性 DC 在此过程中发挥的关键作用。此外,DC的体外转染表明IDO足以诱导耐受性表型。当前旨在诱导耐受性的基于 DC 的方案需要在回输给患者之前体外制备和转染自体 DC。因此,该程序的成本和技术挑战似乎是巨大的,需要高度专业化的中心。为了克服这一限制,我们建议使用一种新型的基于纳米结构基因的疫苗递送,该疫苗可有效且特异性地靶向抗原呈递细胞(APC)。因此,我们的策略是基于使用我们的纳米平台选择性靶向 DC,以 DNA 形式与 IDO 一起在体内共同递送疾病相关自身抗原。我们预计,在靶向 DNA 转染后,DC 同时表达胰岛素和 IDO 将诱导耐受性反应,从而减轻/停止胰岛的自身免疫破坏。该平台基于与 MHC II 类结合肽共价缀合的聚酰胺胺 (PAMAM) 树状聚合物(作为 DNA 加载表面),该肽充当靶向 APC(特别是 DC)的配体。该平台将在 NOD 小鼠中进行测试,评估:1)其诱导过继转移的胰岛素特异性 T 细胞耐受的能力;2)其预防糖尿病或糖尿病发作时的治疗功效。所提出的用于体内靶向基因递送的肽-树枝状聚合物平台应产生与传统的 APC 制备方法相同(甚至更高)的耐受性功效,具有相当大的优势,包括:i)低成本(一剂肽-树枝状聚合物估计花费 1 美元),以及 ii)准备和管理简单,减少了对专门中心的需求。此外,通过使用 INS B9-B29 靶向肽,该肽不仅以高亲和力结合 IAg7 MHC II 类分子,而且还结合人类 HLA DQ8 分子,该平台开启了将阳性发现轻松转化为临床的现实可能性。

项目成果

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Paolo Serafini其他文献

Paolo Serafini的其他文献

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{{ truncateString('Paolo Serafini', 18)}}的其他基金

Aptamer mediated silencing of the spliceosome machinery to increase the immunogenicity of metastatic breast cancer
适体介导的剪接体机制沉默以增加转移性乳腺癌的免疫原性
  • 批准号:
    10286216
  • 财政年份:
    2021
  • 资助金额:
    $ 18.04万
  • 项目类别:
Aptamer mediated silencing of the spliceosome machinery to increase the immunogenicity of metastatic breast cancer
适体介导的剪接体机制沉默以增加转移性乳腺癌的免疫原性
  • 批准号:
    10461876
  • 财政年份:
    2021
  • 资助金额:
    $ 18.04万
  • 项目类别:
Antigen-specific tolerance in T1 diabetes by IDO loaded functionalized dendrimers
IDO 负载功能化树枝状聚合物对 T1 糖尿病的抗原特异性耐受
  • 批准号:
    8729563
  • 财政年份:
    2013
  • 资助金额:
    $ 18.04万
  • 项目类别:

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Antigen-specific tolerance in T1 diabetes by IDO loaded functionalized dendrimers
IDO 负载功能化树枝状聚合物对 T1 糖尿病的抗原特异性耐受
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    8729563
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