High-Throughput Evaluation of Dendritic Cell-Targeting Vaccine Particles for the

树突状细胞靶向疫苗颗粒的高通量评估

基本信息

批准号：
8243838
负责人：
Benjamin George Keselowsky
金额：
$ 21.82万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-08 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8243838
关键词：
Antigen-Presenting Cells Antigens Autoimmune Diabetes Autoimmune Diseases Beds Biocompatible Materials Biological Response Modifiers Biomedical Engineering Cell Count Cells Combined Modality Therapy Data Dendritic Cells Dendritic cell activation Development Diabetic mouse Dose Drug Formulations Encapsulated Engineering Evaluation Family Future Glycolic-Lactic Acid Polyester Goals Immune Immune Tolerance Immunology Immunosuppression In Vitro Injectable Injection of therapeutic agent Insulin-Dependent Diabetes Mellitus Libraries Life Link Maps Mediating Medical Methods Organ Transplantation Outcome Particulate Patients Phagocytes Pharmaceutical Preparations Phenotype Polymers Population Prevention Production Regulation Regulatory T-Lymphocyte Research Response to stimulus physiology Role Science Screening procedure Shipping Ships Signal Transduction Solutions Surrogate Markers System Systems Biology T cell response T-Lymphocyte Technology Testing Time Vaccines Vision Work base cell type clinically relevant combinatorial design flexibility high throughput screening immunoregulation improved in vivo innovation miniaturize mouse model novel vaccines particle programs response time use tool uptake vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): This work represents a biomaterials-based biomedical engineering research program integrated with immunology directed toward tolerance. Specifically, this project focuses on the engineering of technologies to provide personalized high-throughput screening of immune cell response to microparticle-based vaccines, using a limited number of cells. Microparticle-based vaccine systems can, in vivo, deliver antigen and relevant immuno- modulatory factors to targeted phagocytic cell population, specifically, dendritic cells, a key immune regulator. Typical assessment of a tolerance-inducing vaccine relies on testing one formulation at a time, hoping to uncover a single factor capable of generating long-lived immune tolerance. However, multiple critical signals are likely to combine to promote robust, enduring antigen-specific tolerance. A lack of understanding of the interactions between different immunomodulatory factors, and the lack of an efficient means to test large numbers of combinations of factors represents a significant blockade for the development of new vaccine technologies. In order to overcome this barrier, we are developing a high-throughput cell-based microarray approach for the testing of microparticles incorporating multiple components targeted to dendritic cells, a key antigen presenting cell type. Our preliminary data indicates that the unique high- throughput in vitro platform we are developing is feasible, and that in vitro screening of microparticle formulations can be useful for suggesting in vivo responses to injected microparticles. Our long-term test-bed application is the prevention of type-1 diabetes in a diabetic mouse model by injection of microparticles. We are optimizing multi- component particle formulations to direct DCs toward a tolerogenic phenotype and the induction of regulatory T-cells for antigen-specific immune suppression. Our miniaturized technology requires only small numbers of cells, taking steps toward the development of personalized vaccines. PUBLIC HEALTH RELEVANCE: We are rapidly in vitro assessing and optimizing antigen-delivering, immuno-modulatory microparticles as an injectable microparticle-based vaccine, intended for targeted uptake in vivo by dendritic cells for future studies for the treatment of type 1 diabetes. Our in vitro system consists of fabricating cell-based microarrays of immune cells for high-throughput screening of microparticle formulations, and formulations will be assessed for their ability to generate immune cell phenotypes which have been linked to the induction of antigen-specific tolerance. This miniaturized approach uses only a small number of cells, and moves toward the development of personalized vaccines, which may be screened for a patient's specific immune cell response.

描述（由申请人提供）：这项工作代表了一项基于生物材料的生物医学工程研究计划，与针对耐受性的免疫学相结合。具体来说，该项目重点关注技术工程，以使用有限数量的细胞对基于微粒的疫苗的免疫细胞反应进行个性化高通量筛选。基于微粒的疫苗系统可以在体内将抗原和相关免疫调节因子递送到目标吞噬细胞群，特别是树突状细胞，这是一种关键的免疫调节剂。对诱导耐受的疫苗的典型评估依赖于一次测试一种配方，希望发现能够产生长期免疫耐受的单一因素。然而，多种关键信号可能结合起来促进强大、持久的抗原特异性耐受。缺乏对不同免疫调节因子之间相互作用的了解，以及缺乏测试大量因子组合的有效手段，严重阻碍了新疫苗技术的开发。为了克服这一障碍，我们正在开发一种基于细胞的高通量微阵列方法，用于测试包含针对树突状细胞（一种关键抗原呈递细胞类型）的多种成分的微粒。我们的初步数据表明，我们正在开发的独特的高通量体外平台是可行的，并且微粒制剂的体外筛选可用于提示对注射微粒的体内反应。我们的长期试验台应用是通过注射微粒在糖尿病小鼠模型中预防 1 型糖尿病。我们正在优化多组分颗粒制剂，以引导 DC 产生耐受性表型，并诱导调节性 T 细胞进行抗原特异性免疫抑制。我们的小型化技术只需要少量的细胞，朝着个性化疫苗的开发迈出了一步。公共健康相关性：我们正在体外快速评估和优化抗原递送、免疫调节微粒作为可注射微粒疫苗，旨在通过树突状细胞进行体内靶向摄取，用于未来治疗 1 型糖尿病的研究。我们的体外系统包括制造基于细胞的免疫细胞微阵列，用于微粒制剂的高通量筛选，并且将评估制剂产生与诱导抗原特异性耐受相关的免疫细胞表型的能力。这种小型化方法仅使用少量细胞，并朝着个性化疫苗的开发方向发展，可以筛选患者的特异性免疫细胞反应。