Systems biology analysis of dendritic cell interactions with biomaterials

描述（由申请人提供）：工程免疫应答将通过解决宿主应答的重大障碍，实现下一代医学治疗的真正潜力。树突状细胞（DC）作为免疫应答的起始和耐受性的维持的守门人的中心作用使得在免疫应答可以在组合产品（例如疫苗递送系统或组织工程策略）中利用的情况下对其表型的控制特别重要。使用生物材料，这些设备的一个组成部分，以指导主机的反应是一个强大的和有远见的战略。Babensee等人已经证明了DC表型的基于生物材料的控制，其具有对体内共递送抗原的免疫应答的调节。因此，在表型谱的相对端，从未成熟（或致耐受性）到成熟的DC，分别期望诱导无应答性/耐受性或增强保护性免疫。DC识别和响应生物材料的基于受体的机制尚不清楚，但是细胞因子、整合素和模式识别受体（PRR）诱导的细胞反应与生物材料诱导的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以启动对生物材料的表型反应。我们的总体假设是，DC识别和响应生物材料的刺激，使用受体的组合，需要一个综合的建模方法来建立多个受体连接签名与DC表型。本提案的目的是：1）开发一种模型，研究DC如何同时整合来自多个受体家族的信息以引发表型可塑性; 2）使用该模型阐明DC用于识别和响应生物材料的关键受体家族。我们将实现一个整体的理解与DC生物材料的反应，包括协同作用，这是不可行的，一次看一个途径的全局视图。本提案中使用的方法是将DC视为具有传递的刺激/输入、采样的中间信号和测量的输出/响应的系统，以开发统计模型。因此，该建议应用了以前采用的系统生物学方法，开发的Lauffenberger，Janes和肯普，在一个新的能力，解决"逆"的问题，识别受体使用的DC感测生物材料。具体目标1将为已知受体驱动的DC表型结果建立信号传导和细胞因子谱的整合模型。具体目标2将确定DC响应特定生物材料的受体基础。具体目标3将验证介导DC对特定生物材料的反应的受体家族的作用。该项目的完成将为未来研究生物材料背景下的知情工程DC驱动免疫反应提供框架。它也将提供一个背景下，深入研究的个别受体与DC生物材料的反应中起主导作用。

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.