Testing the role of B cell receptor signalling in germinal centre responses

在我们高度流动的社会中，由于旅行增加、全球移徙改变和食物链安全降低，传染病的风险正在增加。疫苗接种是一种具有成本效益的方法，可以预防感染。然而，接种疫苗并不总是保证完全预防感染，这在幼儿和老年人中尤其如此。随着寿命的延长，到2034年，预计四分之一的英国人口将超过65岁，这一问题将继续成为预防医学的前沿。疫苗接种反应减少的主要原因之一是免疫系统在极端年龄时受损。尽管人们对其中一个原因知之甚少，但其中一个原因是B细胞功能不佳，B细胞是产生抗体的免疫细胞，有助于识别和清除病原体，从而防止感染。产生长寿命的病原体特异性B细胞是大多数疫苗接种的基础。当一种新的病原体或疫苗进入人体时，B细胞通过产生抗体做出反应，重要的是，它们通过一个被称为“亲和成熟”的优化过程进行调节，不断尝试提高它们产生的抗体的质量。这个过程类似于进化，B细胞经历了反复的抗体基因突变，然后选择“最适合”的B细胞来产生最能对付病原体的抗体。近年来，亲和成熟是如何起作用的一直受到密切关注，我们知道它涉及B细胞接受其他免疫细胞，即T细胞的帮助。我们不了解的是B细胞与病原体或疫苗的直接相互作用是如何形成这一过程的，有了这一缺失的信息，我们应该能够开发出完全不同的疫苗接种方法，以提高抗体产生的数量和质量，例如在老年人中。这个项目的最终目的是了解B细胞和抗体选择过程是如何被调节的，从而使我们能够生产出更好的疫苗。这将通过与Medimmune公司的合作来实现，该公司将帮助生产亲和性成熟增强的转基因小鼠。除了帮助开发更好的疫苗外，这些小鼠将成为寻求生产新的单克隆抗体疗法的工业的宝贵工具，因为产生新的单克隆抗体的过程本身就涉及疫苗接种。与Medimmune的联系将确保他们在动物模型生成方面的能力与Toellner博士在B细胞和疫苗接种生物学方面的知识相结合，从而产生一个项目，将导致该领域的一个步骤变化，并产生对研究人员和工业界都有用的资源。

In our highly mobile society the risks from infectious diseases are increasing due to increased travel, altered global migration and reduced security in the food-chain. Vaccination is a cost-effective approach that can protect against infection. However, vaccination does not always guarantee complete protection against infection and this is especially true in the very young and the elderly. As longevity is increasing, by 2034 it is estimated that 1 in 4 of the UK population will be aged over 65, this issue will continue to be at the forefront of preventive medicine. One of the main reasons for reduced vaccination responses is that the immune system is impaired at the extremes of age. Although poorly understood one cause is poor functioning of B cells, the immune cells that produce the antibodies that help identify and remove pathogens and thus prevent infection. Production of long lived pathogen-specific B cells is the basis of most vaccinations. When a new pathogen or vaccine enters the body B cells respond by producing antibody and importantly they are conditioned through an optimization process called "affinity maturation" to continually try to improve the quality of the antibody they make. The process is akin to evolution in that B cells undergo repeated rounds of antibody gene mutation followed by selection of the "fittest" B cells to produce antibody that will best deal with the pathogen. How affinity maturation works has been under intense scrutiny over recent years and we know that it involves B cells receiving help from other immune cell, namely T cells. What we do not understand is how the direct interaction of B cells with the pathogen or vaccine shapes this process and having this missing piece of information should allow us to develop radically different approaches to vaccinations to improve the quantity and quality of antibody produced for example in older adults. The ultimate aim of this project is to understand how this B cell and antibody selection process is regulated to allow us to produce better vaccines. This will be achieved through collaboration with the company Medimmune who will help to produce genetically modified mice where affinity maturation is enhanced. In addition to helping develop better vaccines, these mice will become valuable tools for industry in the quest to produce new monoclonal antibody therapeutics, as the process of generating new monoclonal antibodies itself involves vaccination. The link with Medimmune will ensure that their capacity in animal model generation is integrated with Dr Toellner's knowledge of B cell and vaccination biology, to produce a project that will lead to a step change in the field and generate resources useful to researchers and industry alike.