Bioengineered siRNA/Nanoparticles to Prevent Human Transplant Rejection

生物工程 siRNA/纳米颗粒可防止人体移植排斥

基本信息

  • 批准号:
    8693080
  • 负责人:
  • 金额:
    $ 29.1万
  • 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:
    2013-08-01 至 2015-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): We propose to apply methods and insights of bioengineering and human immunology to a surgical therapy, namely organ transplantation. Our goal is to produce safe, efficient, selective and sustained knock down of immunostimulatory proteins within human graft endothelial cells (EC) by developing ex vivo targeted nanoparticle transfection of siRNA so as to reduce allograft rejection in humanized pre-clinical models. Rejection remains an important cause of graft loss and current regimens of host immunosuppression produce significant complications. Our novel approach will reduce rejection instead by modifying the alloantigenicity of the graft. By focusing on human-based models, we address two fundamental limitations of most rodent transplant models. First, adult humans, but not experimental rodents, have circulating effector memory T cells capable of directly recognizing non-self-major histocompatibility complex (MHC) molecules and, upon activation, causing graft rejection. The high frequency of alloreactive memory cells is thought to account for the failure in humans of many therapies successful in rodents. Second, human endothelial cells (ECs), unlike rodent ECs, express and directly present non-self-class II MHC molecules to circulating effector memory T cells, initiating rejection and bypassing the need for graft dendriti cells ("passenger leukocytes") to activate na¿ve host T cells seen in rodent models. Our experiments with cultured human ECs and with humanized mouse models of allograft rejection have revealed crucial roles for EC-expressed co-stimulators and EC- derived cytokines as well as EC-expressed MHC molecules in T cell activation. Furthermore, human effector memory T cells are still somewhat plastic and can be irreversibly directed along different pathways by their initial contact with graft ECs. In other words, changes in the expression of immune stimulatory or regulatory molecules by ECs in the perioperative period can have lasting effects on graft outcomes. In current clinical practice, the graft vasculature is flushed with an organ preservation solution so that ECs throughout the graft come in contact with the perfusate. We will optimize conditions for ex vivo delivery of siRNAs using biodegradable polymer nanoparticles engineered to efficiently transfect ECs lining human blood vessels and to produce a more sustained change in the EC phenotype achieved by current transfection approaches (specific aim 1); we will use this approach to knock down specific immunomodulatory molecules, examples being CIITA, LFA-3, raptor and/or IL-1a, in cultured human ECs and assess effects on the activation of allogeneic memory T cells in vitro, compared to conventional EC transfections (specific aim 2); and we will use nanoparticle- mediated transfection to knock down molecules identified as important in aim 2 in the ECs lining human artery segments ex vivo prior to implantation into mice reconstituted with a human immune system allogeneic to the artery donor, assessing the effect on acute and subacute graft rejection (specific aim 3). These pre-clinical studies will provide proof of concept for our novel approach to improve the outcome of allotransplantation.
描述(由申请人提供):我们提出将生物工程和人类免疫学的方法和见解应用于外科治疗,即器官移植。我们的目标是通过开发siRNA的离体靶向纳米颗粒转染,在人移植物内皮细胞(EC)内产生安全、有效、选择性和持续的免疫刺激蛋白敲低,以减少人源化临床前模型中的同种异体移植物排斥。排斥反应仍然是移植物丢失的重要原因,目前的宿主免疫抑制方案产生严重的并发症。我们的新方法将通过改变移植物的同种抗原性来减少排斥反应。通过关注基于人类的模型,我们解决了大多数啮齿动物移植模型的两个基本限制。首先,成年人,而不是实验啮齿动物,具有能够直接识别非自身主要组织相容性复合体(MHC)分子的循环效应记忆T细胞,并在激活后引起移植排斥。同种异体反应性记忆细胞的高频率被认为是许多在啮齿动物中成功的疗法在人类中失败的原因。其次,与啮齿动物EC不同,人类内皮细胞(EC)表达并直接将非自身II类MHC分子呈递给循环效应记忆T细胞,引发排斥反应并绕过对移植树突状细胞(“乘客白细胞”)的需要以激活啮齿动物模型中观察到的幼稚宿主T细胞。我们用培养的人EC和用同种异体移植排斥的人源化小鼠模型的实验已经揭示了EC表达的共刺激因子和EC衍生的细胞因子以及EC表达的MHC分子在T细胞活化中的关键作用。此外,人效应记忆T细胞仍然具有一定的可塑性,并且可以通过它们的功能沿着沿着不同的途径不可逆地定向。 与移植物内皮细胞初次接触。换句话说,围手术期EC免疫刺激或调节分子表达的变化可能对移植结果产生持久影响。在目前的临床实践中,移植血管系统用器官保存冲洗, 使移植物中EC与灌注液接触。我们将优化使用可生物降解的聚合物纳米颗粒进行siRNA离体递送的条件,所述纳米颗粒被工程化以有效地转染人类血管内衬的EC,并通过当前的转染方法实现EC表型的更持续的改变。(具体目标1);我们将使用这种方法来敲低特定的免疫调节分子,例如CIITA、LFA-3、raptor和/或IL-1 a,在培养的人EC中,并评估与常规EC转染相比,(具体目标2);我们将使用纳米粒子介导的转染,以在植入用人免疫重建的小鼠之前,在离体的人动脉段内衬的EC中敲低在目的2中被鉴定为重要的分子系统同种异体动脉供体,评估对急性和亚急性移植排斥反应的影响(具体目标3)。这些临床前研究将为我们改善同种异体移植结果的新方法提供概念证明。

项目成果

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{{ truncateString('JORDAN S POBER', 18)}}的其他基金

Ex Vivo Nanoparticle Drug Delivery Targeted to Human Allograft Endothelium
针对人同种异体移植物内皮的体外纳米颗粒药物输送
  • 批准号:
    10783379
  • 财政年份:
    2023
  • 资助金额:
    $ 29.1万
  • 项目类别:
Assessment of immunogenicity and antigenicity of different human cell types in natural and 3D-printed allografts
评估天然和 3D 打印同种异体移植物中不同人类细胞类型的免疫原性和抗原性
  • 批准号:
    10353416
  • 财政年份:
    2021
  • 资助金额:
    $ 29.1万
  • 项目类别:
Assessment of immunogenicity and antigenicity of different human cell types in natural and 3D-printed allografts
评估天然和 3D 打印同种异体移植物中不同人类细胞类型的免疫原性和抗原性
  • 批准号:
    10194232
  • 财政年份:
    2021
  • 资助金额:
    $ 29.1万
  • 项目类别:
Ex Vivo Nanoparticle Drug Delivery Targeted to Human Renal Allograft Endothelium
针对人肾同种异体移植物内皮的体外纳米颗粒药物输送
  • 批准号:
    10197784
  • 财政年份:
    2017
  • 资助金额:
    $ 29.1万
  • 项目类别:
Ex Vivo Nanoparticle Drug Delivery Targeted to Human Renal Allograft Endothelium
针对人肾同种异体移植物内皮的体外纳米颗粒药物输送
  • 批准号:
    10155842
  • 财政年份:
    2017
  • 资助金额:
    $ 29.1万
  • 项目类别:
Optimizing Therapeutic Revascularization by Endothelial Cell Transplantation
通过内皮细胞移植优化治疗性血运重建
  • 批准号:
    9516109
  • 财政年份:
    2017
  • 资助金额:
    $ 29.1万
  • 项目类别:
Targeting Nanoparticles for Drug Delivery to Renal Graft Endothelium during Ex Vivo Normothermic Perfusion
体外常温灌注期间靶向纳米颗粒将药物递送至肾移植物内皮
  • 批准号:
    9164300
  • 财政年份:
    2016
  • 资助金额:
    $ 29.1万
  • 项目类别:
Spatiotemporal Delivery of miRNA Anatgomir for Promoting Vascular Self-Assembly
miRNA Anatgomir 的时空传递促进血管自组装
  • 批准号:
    8322816
  • 财政年份:
    2011
  • 资助金额:
    $ 29.1万
  • 项目类别:
Controlled Spatiotemporal Delivery of miRNA Anatgomir for Promoting Vascular Self
受控时空递送 miRNA Anatgomir 以促进血管自身
  • 批准号:
    8138278
  • 财政年份:
    2011
  • 资助金额:
    $ 29.1万
  • 项目类别:
SCID Mouse: Human Xenograft Core
SCID 小鼠:人类异种移植核心
  • 批准号:
    7608570
  • 财政年份:
    2008
  • 资助金额:
    $ 29.1万
  • 项目类别:

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