Decoding vomocytosis for cell-medaited, intra-lymph nodal delivery of microparticle vaccines

解码胞浆作用以实现细胞介导的微粒疫苗的淋巴结内递送

• 批准号: 9924928
• 负责人: Jamal S Lewis
• 金额: $ 5.88万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924928
• 关键词: Adaptive Immune System; Behavior; Biochemistry; Biocompatible Materials; Biological Process; Biophysics; Cell physiology; Cells; Cryptococcus neoformans; Cytoplasm; Dendritic Cells; Development; Disease; Drug Delivery Systems; Engineering; Environment; Enzymes; Exocytosis; Foundations; Goals; Immune; Immune system; Immunology; Immunotherapeutic agent; Infectious Agent; Instruction; Investigation; Laboratories; Lymph; Lymphatic; Lymphatic vessel; Mediating; Mission; Motivation; National Institute of General Medical Sciences; Nodal; Nonlytic; Organ; Particulate; Particulate Matter; Pathology; Peripheral; Phagocytes; Phagocytosis; Phagosomes; Prevention; Process; Reactive Oxygen Species; Reporting; Research; Research Support; System; Tissues; Vaccines; Vacuole; Vesicle; Work; Zika Virus; design; disease diagnosis; global health; health organization; immunoregulation; lymph nodes; macrophage; mimetics; multidisciplinary; next generation; novel; particle; programs; prophylactic; research and development; trafficking; uptake; vaccine delivery; vaccinology

DECODING VOMOCYTOSIS FOR CELL-MEDIATED, INTRA-LYMPH NODAL DELIVERY OF MICROPARTICLE VACCINES ABSTRACT/ SUMMARY The Immuno-modulatory Biomaterials Laboratory at UC Davis focuses on the development of novel biomaterial systems that can manipulate the immune system. Our goal is to design the next generation of immunotherapeutics for applications in immune-related diseases. This multidisciplinary work incorporates aspects of biomaterials engineering, drug delivery, immunology, biochemistry, and cell physiology. One of the main research programs in our lab is understanding controlled vomocytosis (non-lytic exocytosis) of particulate matter from phagocytic cells. Our primary motivation for elucidation of this process is the development of a `smart' microparticle system that can accomplish phagocytic cell-mediated delivery of vaccines directly to the lymph node-residing cells. Phagocytic cells (particularly macrophages [MΦ] and dendritic cells [DCs])) have evolved to circulate through peripheral tissue, engulf foreign particulate matter and traffick to the lymph node following uptake to relay information about the peripheral environment to cellular agents of the adaptive immune system. Evidently, phagocytic cells can transport particulate materials from peripheral tissues to lymphatic organs. Typically, following phagocytosis, and as phagocytic cells traverse the lymphatic vessels, materials that have been engulfed are taken into the phagosome (vacuole in the cytoplasm of a cell containing a phagocytosed particles) where a degradative process occurs due to secretion of reactive oxygen species (ROS), acidic pH and digestive enzymes. This stage would be counterproductive to the integrity of a particulate, and our purpose of intra-lymph nodal delivery. Moreover, release of particles from the phagocytic cell is not an intrinsic quality. But, there is precedent for such behavior. The fungal cell, Cryptococcus neoformans, elicits vomocytosis or (non-lytic exocytosis) from macrophages. There is still little understanding about the mechanisms governing this phenomena. Some reports indicate that there is an increase in pH of the phagosome during this activity, others have suggested Ca2+ flux could be pivotal for vesicle exocytosis. We believe that elucidation of the intra- phagosomal physico-chemical conditions that propel this activity could be instructive for the design of a mimetic microparticle. Further, investigation of the transcriptomal signatures between the period of phagocytosis and exocytosis could give us clues as to what biophysical factors are altered in the phagosome. Ultimately, our long- term goal is develop universally-deployable, microparticle vaccine platform as an effective, long-lasting prophylactic against infectious agents. The research and development of this platform system has the potential to significantly transform the treatment of a plethora of immune pathologies. Therefore, the proposed program is highly relevant to the mission of the National Institute of General Medical Sciences (NIGMS), which pertains to supporting research that increases understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment and prevention.

解码细胞介导的细胞介导的淋巴内淋巴结递送微粒疫苗的胞吐作用 摘要/总结 加州大学戴维斯分校的免疫调节生物材料实验室专注于新型药物的开发 可以操纵免疫系统的生物材料系统。我们的目标是设计下一代 免疫疗法在免疫相关疾病中的应用。这项多学科工作包括 生物材料工程、药物输送、免疫学、生物化学和细胞生理学等方面。中的一个 我们实验室的主要研究项目是了解颗粒的受控胞吐作用（非溶解性胞吐作用） 来自吞噬细胞的物质。我们阐明这一过程的主要动机是开发“智能” 可以完成吞噬细胞介导的将疫苗直接递送至淋巴的微粒系统 节点驻留细胞。吞噬细胞（特别是巨噬细胞 [MΦ] 和树突状细胞 [DC]））已进化到 通过周围组织循环，吞噬外来颗粒物质并运输至淋巴结 摄取将有关周围环境的信息传递给适应性免疫系统的细胞因子。 显然，吞噬细胞可以将颗粒物质从周围组织转运到淋巴器官。 通常，在吞噬作用之后，当吞噬细胞穿过淋巴管时，物质 被吞噬的物质被带入吞噬体（含有被吞噬的细胞的细胞质中的液泡） 由于活性氧 (ROS) 的分泌、酸性 pH 值和 消化酶。这个阶段会对颗粒的完整性产生反作用，而我们的目的是 淋巴结内递送。此外，吞噬细胞释放颗粒并不是一种内在品质。但， 这种行为是有先例的。真菌细胞，新型隐球菌，引起胞吐作用或（非裂解性） 巨噬细胞的胞吐作用）。对于控制这一现象的机制仍然知之甚少 现象。一些报告表明，在此活动期间，吞噬体的 pH 值增加，其他报告表明 表明 Ca2+ 通量可能是囊泡胞吐作用的关键。我们相信，内部的澄清 促进这种活动的吞噬体物理化学条件可能对模拟物的设计具有指导意义 微粒子。此外，对吞噬阶段和吞噬阶段之间的转录特征的研究 胞吐作用可以为我们提供有关吞噬体中哪些生物物理因素发生改变的线索。最终，我们的长期 长期目标是开发可普遍部署的微粒疫苗平台，作为一种有效、持久的疫苗 针对传染性病原体的预防措施。该平台系统的研发具有潜力 显着改变多种免疫病理的治疗方法。因此，拟议的计划是 与国家普通医学科学研究所 (NIGMS) 的使命高度相关，该研究所涉及 支持可增进对生物过程的理解并为进步奠定基础的研究 在疾病的诊断、治疗和预防方面。