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Development and application of an in vitro blood-brain barrier model to investigate intravenous immunoglobulin therapy for Alzheimer's disease.

机译：开发和应用体外血脑屏障模型研究阿尔茨海默氏病的静脉免疫球蛋白治疗。

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摘要

One of the largest and fastest growing sectors in the global pharmaceutical industry is the development of treatments for diseases of the central nervous system. Unfortunately, current systemically administered medications do not achieve optimum therapeutic efficacy in the brain due to limitations in crossing the blood-brain barrier (BBB). Further research is needed to enhance the understanding of how and what molecules can pass through the BBB, and the creation of an in vitro BBB model is crucial to study the cellular constituents and the dynamic capabilities of the BBB that are difficult or nearly impossible to resolve in vivo. The most prevalent BBB model consists of a monolayer of endothelial cells grown on a porous membrane submerged in the wells of a multi-well plate. The large range of cell types available, cell culture variable set points (species, generation, co-culture setup), and system variable set points (membrane configuration, media composition) has resulted in an expansive number of unique models in the field. The significance of our work lies in presenting an in vitro BBB model based on a rational understanding of model configurations and applicability for advancing brain therapeutic research. The first objective of this research was to construct an optimal in vitro BBB model by statistically screening model parameter set points using primary and immortalized murine endothelial cells and astrocytes. Two sets of sequential screening experiments identified optimal cell culture growth parameter set points and an optimal membrane configuration, which increased model performance 4-fold. The second objective of our work applied this optimized model to investigate BBB phenomena occurring in Alzheimer's disease (AD) and its treatment with intravenous immunoglobulin (IVIG) therapy, a passive immunotherapeutic under investigation for AD in human clinical trials. We quantified IVIG transport into the brain in the presence of Abeta peptides and assessed the subsequent effects on decreasing inflammation. IVIG accumulated in the brain side at physiologically relevant levels and was found to decrease inflammation when low Abeta levels were present. In conclusion, the optimized in vitro BBB model is a valuable tool for efficiently advancing the study of brain diseases and their potential therapeutics.
机译：在全球制药工业中，最大和增长最快的部门之一是开发中枢神经系统疾病的治疗方法。不幸的是，由于穿越血脑屏障（BBB）的局限性，目前全身使用的药物无法在大脑中达到最佳治疗效果。需要进一步的研究来增进对分子如何以及通过BBB的理解，建立体外BBB模型对于研究难以或几乎无法解析的BBB的细胞成分和动态能力至关重要。体内。最流行的BBB模型由生长在多孔板中的多孔膜上生长的单层内皮细胞​​组成。可用的细胞类型种类繁多，细胞培养变量设置点（种类，世代，共培养设置）和系统变量设置点（膜配置，培养基组成）导致了该领域中众多独特的模型。我们工作的意义在于提出一种基于对模型配置的合理理解和体外脑治疗研究的适用性的体外BBB模型。这项研究的第一个目标是通过使用原代和永生化鼠类内皮细胞和星形胶质细胞统计筛选模型参数设定点来构建最佳的体外BBB模型。两组连续的筛选实验确定了最佳的细胞培养生长参数设定点和最佳的膜配置，从而将模型性能提高了4倍。我们工作的第二个目标是应用此优化模型来研究在阿尔茨海默氏病（AD）中发生的血脑屏障现象及其通过静脉免疫球蛋白（IVIG）治疗进行的治疗，这是一项在人类临床试验中正在研究的针对AD的被动免疫疗法。我们量化了在存在Abeta肽的情况下IVIG转运入大脑的过程，并评估了其对减轻炎症的后续影响。 IVIG以生理上相关的水平积聚在脑侧，并发现当存在低Abeta水平时，IVIG可以减少炎症。总之，优化的体外BBB模型是有效推进脑疾病及其潜在治疗方法研究的宝贵工具。

著录项

  • 作者

    Wuest, Diane Marie.;

  • 作者单位

    University of Delaware.;

  • 授予单位 University of Delaware.;
  • 学科 Engineering Chemical.;Chemistry Biochemistry.;Biology Neuroscience.
  • 学位 D.Eng.
  • 年度 2014
  • 页码 354 p.
  • 总页数 354
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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