Systems biology analysis of dendritic cell interactions with biomaterials

描述(由申请人提供)：工程免疫反应将通过解决宿主反应的重大障碍，实现下一代医疗治疗的真正潜力。树突状细胞(DC)作为启动免疫反应和维持耐受性的守门人的核心作用，使得在免疫反应可用于组合产品(如疫苗递送系统或组织工程策略)的情况下，对其表型的控制尤为重要。使用生物材料，这些设备的一个组成部分，来指导宿主的反应是一个强大的和有远见的战略。Babensee等人已经证明了基于生物材料的DC表型控制，通过调节体内对共同递送抗原的免疫反应。因此，处于表型谱相反两端的DC，从不成熟(或耐受性)到成熟，分别是诱导无应答/耐受或增强保护性免疫的理想选择。DC识别和响应生物材料的受体机制尚不清楚，但细胞因子、整合素和模式识别受体(PRR)诱导的细胞反应和生物材料诱导的DC成熟之间的共性表明，DC参与这些外部传感受体家族的组合来启动对生物材料的表型反应。我们的总体假设是，DC使用一组受体识别并响应生物材料刺激，这就需要一种综合的建模方法来建立与DC表型相关的多个受体连接特征。该建议的目的是1)建立一个模型，说明DC如何同时整合来自多个受体家族的信息，以获得表型可塑性；2)使用该模型来阐明DC识别和响应生物材料的关键受体家族。我们将实现对DC对生物材料的响应的全球视角的综合理解，包括协同作用，这是不可行的，一次只看一条途径。本提案中使用的方法是将DC视为一个系统，其中包含传递的刺激/输入、采样的中间信号和测量的输出/响应，以开发统计模型。因此，这一建议应用了Lauffenberger，Janes和Kemp开发的先前采用的系统生物学方法，以一种新的能力来解决识别DC用来感知生物材料的受体的“逆”问题。特定目标1将为已知受体驱动的DC表型结果建立一个信号和细胞因子谱的综合模型。特定目标2将确定DC对特定生物材料的反应的受体基础。具体目标3将验证受体家族在介导DC对特定生物材料的反应中的作用。该项目的完成将在生物材料的背景下为未来的研究提供一个知情工程DC驱动的免疫反应的框架。它还将为深入研究在DC对生物材料的反应中起主导作用的单个受体提供背景。

DESCRIPTION (provided by applicant): Engineering immune responses will enable achievement of the true potential of the next generation of medical treatments by addressing the significant barrier of the host response. The central role of dendritic cells (DCs) as gatekeepers to the initiation of immune responses and maintenance of tolerance renders the control of their phenotype particularly important in situations where immune responses can be harnessed in combination products, such as vaccine delivery systems or tissue engineering strategies. Using biomaterials, an integral component of these devices, to direct the host response is a powerful and visionary strategy. Babensee et al have demonstrated biomaterial-based control of DC phenotype with modulation of immune responses to co- delivered antigen in vivo. As such, DCs at opposite ends of the phenotypic spectrum, from immature (or tolerogenic) to mature, are desirable to either induce non-responsiveness /tolerance or enhance protective immunity, respectively. The receptor-based mechanisms by which DCs recognize and respond to biomaterials is unknown, however commonalities between the cytokine, integrin, and pattern recognition receptor(PRR)-induced cellular responses and biomaterial-induced DC maturation, suggest that DCs engage a combination of these external sensing receptor families to initiate phenotypic responses to biomaterials. Our overall hypothesis is that DCs recognize and respond to biomaterial stimuli using a combination of receptors, necessitating an integrative modeling approach to establish multiple receptor ligation signatures associated with DC phenotypes. The objectives of this proposal are to 1) develop a model of how DCs integrate information from multiple receptor families concurrently to elicit phenotypic plasticity and 2) use this model to elucidate the key receptor families used by DCs to recognize and respond to biomaterials. We will achieve an integrative understanding with a global view of DC responses to biomaterials, including synergistic interactions, which is not feasible looking at one pathway at a time. The approach used in this proposal is to treat the DC as a system with delivered stimuli/inputs, sampled intermediate signals, and measured outputs/responses to develop a statistical model. This proposal thus applies a previously employed systems biology approach, developed by Lauffenberger, Janes and Kemp, in a novel capacity of addressing the "inverse" problem of identifying receptors used by DCs to sense biomaterials. Specific aim 1 will establish an integrative model of signaling and cytokine profiles for known receptor-driven DC phenotypic outcomes. Specific aim 2 will identify the receptor basis for DC responses to specific biomaterials. Specific aim 3 will validate role of receptor families mediating DC responses to specific biomaterials. Completion of this project will provide a framework for informed engineering DC-driven immune responses in the context of biomaterials for future studies. It will also provide a context for in-depth study of individual receptors with a dominant role in DC responses to biomaterials.