Microparticles for Directing Immune Cell Trafficking

 描述（由申请方提供）：许多病原体进化出复杂的方法来影响免疫细胞的趋化行为，以在宿主中定植。恢复和可预测地操纵免疫细胞趋化性的技术的发展可以导致传染病治疗的生物医学突破。一种有前途的方法是局部工程化趋化因子（CK）梯度，目的是促进关键免疫参与者的积累或引发免疫反应的级联反应，以消除病原体或肿瘤。为此，我们建议使用我们最近发明的新的多功能微米和纳米颗粒（NP）平台技术。纳米颗粒由水凝胶支架与各种内部诱饵化学偶联组成，这些诱饵能够在一个步骤中捕获并保护各种分子免受其环境的降解。此外，NP可以负载有可以以受控速率从诱饵可逆释放的药物活性物质。基于这个平台，我们提出了一种简单而通用的方法来创建CK负载的NPs，这可以作为一个研究工具和未来的免疫疗法的原型，用于操纵白细胞运输。本项目的主要目标是证明使用NP技术的CK梯度重建方法的可行性。作为第一步，我们将在体内环境中模拟纳米颗粒，以研究选择用于靶向参与免疫应答感染的中性粒细胞的四种CK负载的纳米颗粒的持续释放的药效学。接下来，我们将证明负载CK的NP在皮下给予B后增加白细胞募集到引流淋巴结的能力。将炭疽孢子作为感染性疾病的模型给予小鼠，该感染性疾病在免疫细胞的募集方面具有众所周知的异常。为了获得对淋巴结内感染的宿主反应及其通过给予CK的调节的新见解，我们将对来自感染的淋巴结的淋巴液进行全局蛋白质组学分析。我们的用于体内递送的负载趋化因子的纳米颗粒，加上感染期间淋巴蛋白质组的全局阐明，将极大地增加我们对细菌发病机制和宿主细胞对感染病原体的免疫反应的理解。

 DESCRIPTION (provided by applicant): Many pathogens evolved sophisticated means to influence the chemotactic behavior of immune cells for colonization of the host. Development of technology to restore and predictably manipulate the chemotaxis of immune cells can lead to biomedical breakthroughs for infectious disease treatment. A promising approach is to locally engineer chemokine (CK) gradients with the goal of promoting the accumulation of key immune players or eliciting cascades of immune responses to eliminate pathogens or tumors. For this purpose we propose using a new multifunctional micro- and nanoparticle (NP) platform technology recently invented by us. The NPs consist of a hydrogel scaffold chemically coupled with a variety of inner baits capable of capturing and protecting from degradation a wide range of molecules from their environment in one step. In addition, the NPs can be loaded with pharmacoactive substances that can be reversibly released from the baits with a controlled rate. Based on this platform we propose a simple and versatile approach for creating CK-loaded NPs which could serve both as a research tool and a prototype of future immunotherapies for manipulating leukocyte trafficking. The main goal of this project is to demonstrate feasibility of the CK gradient remodeling approach using our NP technology. As the first step we will model the nanoparticles' in an in vivo environment to study the pharmacodynamics of sustained release of four CK-loaded NPs chosen to target neutrophils participating in the immune response infections. Next, we will demonstrate the capacity of CK-loaded NPs to increase leukocyte recruitment to draining lymph nodes after subcutaneous administration of B. anthracis spores to mice as a model of an infectious disease with well-known abnormalities in the recruitment of immune cells. To gain new insights into host responses to infection within lymph nodes and their modulation by administered CKs we will carry out global proteomic analysis of lymph from the infected LNs. Our chemokine-loaded nanoparticles for in vivo delivery, coupled with global elucidation of the lymph proteome during infection will vastly increase our understanding bacterial pathogenesis and host cellular immune response to infecting pathogens.