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A Comprehensive Platform for T-Cell Stimulation Based on Biodegradable Polymeric Artificial Antigen-Presenting Cells.

机译：基于可生物降解的高分子人工抗原呈递细胞的T细胞刺激综合平台。

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摘要

Artificial antigen-presenting cells (aAPCs) are synthetic particles that mimic the action of professional antigen-presenting cells during interactions with T cells. aAPCs offer advantages over the use of live cells to stimulate T cells in vitro; however, current aAPC systems lack one or more of the three necessary signals for physiological T-cell stimulation: recognition, costimulation, and soluble cytokine signals. We incorporated these signals in a biodegradable aAPC constructed from poly(lactide-co-glycolide), a safe polymer with established use in humans. Our aAPCs present a high density of adaptor elements for attaching recognition and costimulatory ligands to a biodegradable core encapsulating the cytokine interleukin-2 (IL-2). Sustained release of IL-2 from aAPCs simulates a physiologic paracrine mode of IL-2 delivery and dramatically improves the stimulatory capacity of this system compared to bulk addition of cytokine.;We demonstrate that biodegradable aAPCs are capable of delivering all three essential signals to T cells, resulting in a 45-fold expansion of murine T cells after four days. Controlled release of IL-2 from aAPCs delivering nanogram quantities of IL-2 increases the potency of the cytokine by more than 1000-fold by creating and maintaining high local concentrations in the vicinity of T cells. Varying spatiotemporal aspects of IL-2 delivery revealed that paracrine IL-2 delivery signals CD8+ T cells to proliferate but results in CD4+ T-cell apoptosis due to activation-induced cell death. The effects of paracrine IL-2 aAPCs depend on nanometer-scale contact between T cells and aAPCs and continued release of picogram levels of IL-2. Furthermore, aAPC diameter is an important parameter dictating the potency of aAPCs; micro-scale aAPCs are 50% more potent than nano-scale aAPCs.;The aAPC developed in this thesis is the first platform to delivering sustained and controlled cytokine signals with T cell recognition and costimulation, and its use revealed intrinsic differences in the response of CD4+ and CD8+ T cells to paracrine IL-2 delivery. This finding has implications for understanding T cell communication in vivo and for the design of T cell-targeted therapeutics.
机译：人工抗原呈递细胞（aAPC）是合成颗粒，可在与T细胞相互作用期间模拟专业抗原呈递细胞的作用。与使用活细胞体外刺激T细胞相比，aAPC具有优势。但是，当前的aAPC系统缺少生理性T细胞刺激所需的三个必要信号中的一个或多个：识别，共刺激和可溶性细胞因子信号。我们将这些信号整合到可生物降解的aAPC中，该aAPC由聚丙交酯-共-乙交酯（一种已在人类中广泛使用的安全聚合物）构建而成。我们的aAPC提供了高密度的衔接子元件，用于将识别和共刺激配体连接到包裹细胞因子白介素2（IL-2）的可生物降解的核心。与大量添加细胞因子相比，从aAPC持续释放IL-2可模拟IL-2传递的生理旁分泌模式，并显着改善了该系统的刺激能力。我们证明了可生物降解的aAPC能够将所有三种基本信号传递给T四天后，导致鼠T细胞扩增了45倍。通过递送和维持在T细胞附近的高局部浓度，控制释放a-2纳克的aAPC释放IL-2，可使细胞因子的效力提高1000倍以上。 IL-2传递的时空变化揭示了旁分泌IL-2传递信号CD8 + T细胞增殖，但由于激活诱导的细胞死亡而导致CD4 + T细胞凋亡。旁分泌IL-2 aAPCs的作用取决于T细胞与aAPCs之间的纳米级接触以及皮尔克水平IL-2的持续释放。此外，aAPC直径是决定aAPC效能的重要参数。微米级aAPC的效能比纳米级aAPC高50％。；本论文开发的aAPC是第一个通过T细胞识别和共刺激传递持续和受控细胞因子信号的平台，其使用揭示了反应的内在差异。 CD4 +和CD8 + T细胞可分泌旁分泌IL-2。这一发现对理解体内T细胞通讯和设计针对T细胞的治疗药物具有重要意义。

著录项

  • 作者

    Steenblock, Erin Rae.;

  • 作者单位

    Yale University.;

  • 授予单位 Yale University.;
  • 学科 Engineering Biomedical.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 175 p.
  • 总页数 175
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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