Microparticles for Directing Immune Cell Trafficking

用于指导免疫细胞运输的微粒

• 批准号: 8869906
• 负责人: Virginia Anne Espina
• 金额: $ 18.98万
• 依托单位: GEORGE MASON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869906
• 关键词: Affinity; Anthrax disease; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Area; Attention; Bacillus anthracis spore; Behavior; Binding; Biological; Biological Preservation; Biological Process; CCL2 gene; CCL3 gene; CCL4 gene; CXCL1 gene; Cells; Chemicals; Chemistry; Chemotaxis; Communicable Diseases; Communication; Complex; Coupled; Dendritic Cells; Engineering; Ensure; Environment; Future; Goals; Host Defense; Hydrogels; Immune; Immune Cell Suppression; Immune response; Immunomodulators; Immunotherapy; In Vitro; Infection; Inflammatory; Kinetics; Lead; Leukocyte Trafficking; Leukocytes; Lymph; Lymphoid; Methodology; Modeling; Mus; Nanotechnology; Nature; Neoplasm Metastasis; One-Step dentin bonding system; Organ; Outcome; Pathogenesis; Pathology; Pharmacodynamics; Physiological; Play; Population; Procedures; Process; Proteins; Proteoglycan; Proteome; Proteomics; Reagent; Research; Secondary to; Signal Transduction; Source; Structure; System; Technology; Testing; Therapeutic; Therapeutic Studies; Tissues; Tumor Antigens; Vaccine Adjuvant; anthrax toxin; antimicrobial; base; chemokine; controlled release; design; improved; in vivo; infectious disease model; infectious disease treatment; innovation; insight; interest; lymph nodes; macrophage; microorganism antigen; migration; mouse model; nanoparticle; neutrophil; novel; novel vaccines; particle; pathogen; polyacrylamide hydrogels; prototype; public health relevance; receptor; research study; scaffold; subcutaneous; technology development; therapeutic development; tool; trafficking; tumor

 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.

 描述（由申请人提供）：许多病原体进化出复杂的手段来影响免疫细胞在宿主定殖时的趋化行为。恢复和可预测地操纵免疫细胞趋化性的技术的发展可以为传染病治疗带来生物医学突破。一种有前途的方法是局部设计趋化因子（CK）梯度，其目标是促进关键免疫参与者的积累或引发级联免疫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型多功能微米和纳米颗粒（NP）平台技术。纳米颗粒由与各种内部诱饵化学偶联的水凝胶支架组成，能够一步捕获环境中的多种分子并防止其降解。此外，纳米颗粒可以负载药用活性物质，这些物质可以以受控的速率从诱饵中可逆地释放。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 NP，它既可以作为研究工具，也可以作为未来操纵白细胞运输的免疫疗法的原型。该项目的主要目标是证明使用我们的 NP 技术进行 CK 梯度重塑方法的可行性。作为第一步，我们将在体内环境中对纳米颗粒进行建模，以研究四种负载 CK 的纳米颗粒持续释放的药效学，这些纳米颗粒被选择用于靶向参与免疫反应感染的中性粒细胞。接下来，我们将证明给小鼠皮下注射炭疽芽孢杆菌孢子后，负载 CK 的 NP 能够增加白细胞募集到引流淋巴结的能力，作为众所周知的免疫细胞募集异常的传染病模型。为了获得关于宿主对淋巴结内感染的反应及其通过施用 CK 进行调节的新见解，我们将对来自受感染淋巴结的淋巴进行全局蛋白质组学分析。我们用于体内递送的负载趋化因子的纳米颗粒，加上感染过程中淋巴蛋白质组的整体阐明，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。