Form Leads to Function: Multi-scale modelling of Lymph Node Architecture in Response to Vaccine Adjuvants

尽管疫苗已经使用了250多年，但推动保护性免疫的机制尚未完全了解。潜在致命的人类和家畜病原体的不断出现，以及生产针对慢性细菌和病毒感染的保护性疫苗的需要，要求我们更好地了解开发下一代疫苗的作用机制。疫苗免疫应答涉及T细胞和B细胞、基质成纤维细胞和组织引流淋巴结（LN）中先天免疫细胞高度多样化的免疫库之间复杂的相互作用。我们已经证明，在免疫应答过程中，LNs在一个依赖于疫苗佐剂类型的过程中快速重塑，调节免疫应答的类型、持续时间和特异性。我们和其他人已经开发了基于多尺度试剂的淋巴结模型，以研究疫苗应答和LN微环境形成过程中的免疫细胞动力学。在这个项目中，我们的目标是使用包括成像、细胞术和不同佐剂基因表达在内的数据集来设计、开发和验证计算模型。我们已经开发了工具包来可视化模型输出和统计分析多尺度计算模型中的参数空间。通过将神经网络仿真与遗传进化算法相结合来执行多目标优化，我们的目标是在计算机上识别出最优的LN结构，从而刺激保护性免疫反应，从而设计出更好的疫苗。益处和项目影响：开发一个强有力的基于证据的疫苗介导免疫反应模型对于了解正常动物和人类淋巴结微环境如何刺激最佳免疫反应以提供长期保护具有重要作用。这有可能开发出针对传染性生物体和癌症的更有效的疫苗。技能训练：学生将有机会学习数学、计算机编程、数据分析以及分子和细胞免疫学等关键的跨学科技能。该学生将在肯尼迪风湿病研究所和数学研究所共同工作，并获得学术和翻译技能培训的机会。肯尼迪和詹纳研究所的跨学科研讨会主办了世界领先的免疫学和疫苗开发研讨会，沃尔夫森数学生物学中心主办了数学生物学研讨会。Simomics是一家总部位于约克的中小企业，它以前开发了虚拟疾病实验室，用于开发利什曼病的治疗方法（LeishSim），并正在开发研究免疫反应的模型。通过这次合作，学生将能够利用Simomics开发的工具，包括虚拟实验室，模型开发语法语言和统计工具包，以协助生成和信任淋巴结模型。一个强大的基于证据的淋巴结模型的发展将提供一个平台来模拟如何产生在健康生活和衰老中起关键作用的最佳疫苗反应。工业借调：借调将在位于约克科学园的Simomics办公室进行。约克是一个充满活力的学术城市，提供了一个美丽的环境。该学生将在一组在软件开发和计算建模方面有丰富经验的软件开发人员中工作。

Although vaccines have been in use for over 250 years, the mechanisms driving protective immunity are not fully understood. The continual emergence of potentially lethal human and domestic animal pathogens, and the need to generate protective vaccines against chronic bacterial and viral infections requires a better understanding of mechanisms of action to develop the next generation of vaccines. Vaccine immune responses involve a complex interplay between the highly diverse immune repertoire of T and B cells, stromal fibroblasts and innate immune cells in tissue draining lymph nodes (LN). We have shown during the immune response, LNs rapid remodel in a process dependent on the type of vaccine adjuvant, regulating the type, duration and specificity of the immune response. We and others have developed multi-scale agent-based models of the lymph node to study immune cell dynamics during vaccine responses and formation of LN microenvironments. In this project we aim to use datasets including imaging, cytometry and gene expression from different adjuvants to design, develop and validate computational models. We have developed tool kits to both visualise model outputs and statistically analyse parameter space in multi-scale computational models. Through combining neural network emulation with genetic evolutionary algorithms to perform multi-objective optimisation, we aim to identify optimal LN architectures in silico that stimulates protective immune responses permitting better vaccine design.Benefits and project impact: Developing a robust evidence-based model of the vaccine mediated immune responses has an essential role in understanding how normal animal and human lymph node microenvironments stimulate optimal immune responses to provide long term protection. This has the potential to permit the development of more effective vaccines for infectious organisms and cancer.Skills Training: The student will have the opportunity to learn key interdisciplinary skills in mathematics, computer programming, data analysis and in molecular and cellular immunology. The student will be jointly based in the Kennedy Institute of Rheumatology and the Mathematical Institute with academic and translational skills training opportunities. Interdisciplinary seminars at the Kennedy and Jenner Institutes host world leading seminars in immunology and vaccine development, the Wolfson Centre for Mathematical Biology in mathematical biology. Simomics is an SME based in York and has previously developed Virtual Disease Laboratories to develop therapeutics for Leishmaniasis (LeishSim) and is working on models to study immune responses. Through this collaboration the student will be able to utilise tools developed by Simomics including virtual laboratories, model development syntax languages and statistical tool kits to assist in the generation and confidence in the lymph node model. Development of a robust evidence-based lymph node model will provide a platform to simulate how to generate optimal vaccine responses that have a critical role in healthy living and aging.Industrial Secondment: The secondment will take place at Simomics offices which based at the York Science Park in York. York is a highly vibrant academic city that provides a beautiful environment. The student will be based in a group of software developers who have extensive experience in software development and computational modelling.