Microparticles for Directing Immune Cell Trafficking

 描述(由申请人提供)：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，以便在宿主上定居。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。一种有希望的方法是局部设计趋化因子(CK)梯度，目的是促进关键免疫角色的积累或引发免疫反应级联，以消除病原体或肿瘤。为此，我们建议使用我们最近发明的一种新的多功能微米和纳米颗粒(NP)平台技术。NPs由水凝胶支架和各种内部诱饵组成，这些诱饵能够在一步内捕获和保护环境中的各种分子不被降解。此外，纳米颗粒可以装载药效物质，可以可逆地从诱饵中以受控的速度释放。基于这一平台，我们提出了一种简单而通用的方法来制备CK负载的NPs，该方法既可以作为研究工具，也可以作为未来操纵白细胞转运的免疫疗法的原型。这个项目的主要目标是证明使用我们的NP技术进行CK梯度重塑的可行性。作为第一步，我们将在体内环境中模拟纳米颗粒，以研究四种加载CK的纳米颗粒的持续释放的药效学，这些纳米颗粒被选为靶向参与免疫反应感染的中性粒细胞。接下来，我们将展示装载CK的NPs在小鼠皮下注射炭疽芽胞后增加白细胞募集到引流淋巴结的能力，作为一种众所周知的免疫细胞募集异常的传染病的模型。为了对宿主对淋巴结内感染的反应及其通过注射CKS的调节有新的了解，我们将对受感染的LNS的淋巴进行全球蛋白质组学分析。我们用于体内递送的趋化因子纳米颗粒，加上感染期间淋巴蛋白质组的全球阐明，将极大地提高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.