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

描述(申请人提供)：这项工作代表了一个以生物材料为基础的生物医学工程研究计划，该计划与免疫学相结合，针对耐受性。具体地说，该项目侧重于利用有限数量的细胞对基于微粒的疫苗提供个性化高通量免疫细胞反应筛查的技术工程。基于微粒的疫苗系统可以在体内将抗原和相关的免疫调节因子输送到靶向吞噬细胞群，特别是作为关键免疫调节因子的树突状细胞。对诱导耐受性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性的单一因素。然而，多个关键信号很可能结合在一起，促进强大的、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发展。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，用于测试以树突状细胞为目标的含有多种成分的微粒，树突状细胞是一种关键的抗原提呈细胞类型。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，体外筛选微粒配方可以有用地建议体内对注射微粒的反应。我们长期的试验台应用是通过注射微粒来预防糖尿病小鼠模型中的1型糖尿病。我们正在优化多组分颗粒配方，以引导DC向耐受表型方向发展，并诱导调节性T细胞进行抗原特异性免疫抑制。我们的微型化技术只需要少量的细胞，朝着个性化疫苗的发展迈出了一步。 与公共健康相关：我们正在快速地在体外评估和优化抗原递送、免疫调节的微粒子作为一种可注射的微粒子疫苗，旨在供树突状细胞体内靶向摄取，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，用于高通量筛选微粒制剂，并将评估其产生免疫细胞表型的能力，这些表型与诱导抗原特异性耐受有关。这种微型化的方法只使用少量的细胞，并朝着个性化疫苗的发展方向发展，这种疫苗可以筛选患者的特定免疫细胞反应。

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.