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

测试 B 细胞受体信号传导在生发中心反应中的作用

• 批准号: BB/M025292/1
• 负责人: Kai-Michael Toellner
• 金额: $ 50.71万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM025292%2F1
• 关键词: Testing; role; cell; receptor; signalling

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.

在我们这个高度移动的社会中，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。接种疫苗是一种具有成本效益的方法，可以防止感染。然而，接种疫苗并不总是保证完全保护免受感染，这在非常年轻和老年人中尤其如此。随着寿命的增加，到2034年，估计英国四分之一的人口将超过65岁，这一问题将继续处于预防医学的前沿。疫苗接种反应降低的主要原因之一是免疫系统在年龄极端时受损。尽管人们对原因知之甚少，但其中一个原因是B细胞功能低下，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。长寿命病原体特异性B细胞的产生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，它们通过称为“亲和力成熟”的优化过程进行调节，以不断尝试改善它们产生的抗体的质量。这一过程类似于进化，B细胞经历反复的抗体基因突变，然后选择“最适合”的B细胞产生最能对付病原体的抗体。亲和力成熟是如何工作的，近年来一直受到严格的审查，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。我们不明白的是，B细胞与病原体或疫苗的直接相互作用是如何塑造这一过程的，拥有这一缺失的信息应该使我们能够开发出完全不同的疫苗接种方法，以提高例如老年人产生的抗体的数量和质量。该项目的最终目的是了解这种B细胞和抗体选择过程是如何调节的，以使我们能够生产更好的疫苗。这将通过与Medimmune公司合作来实现，Medimmune公司将帮助生产增强亲和力成熟的转基因小鼠。除了帮助开发更好的疫苗外，这些小鼠还将成为寻求生产新的单克隆抗体治疗药物的行业的宝贵工具，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博士的B细胞和疫苗接种生物学知识相结合，以产生一个项目，该项目将导致该领域的一步变化，并产生对研究人员和行业有用的资源。

项目成果

Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration.

• DOI: 10.1016/j.celrep.2020.108328
• 发表时间: 2020-11-03
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Jennings E;Elliot TAE;Thawait N;Kanabar S;Yam-Puc JC;Ono M;Toellner KM;Wraith DC;Anderson G;Bending D
• 通讯作者: Bending D

IgG Responses to Porins and Lipopolysaccharide within an Outer Membrane-Based Vaccine against Nontyphoidal Salmonella Develop at Discordant Rates.

• DOI: 10.1128/mbio.02379-17
• 发表时间: 2018-03-06
• 期刊: mBio
• 影响因子: 6.4
• 作者: Schager AE;Dominguez-Medina CC;Necchi F;Micoli F;Goh YS;Goodall M;Flores-Langarica A;Bobat S;Cook CNL;Arcuri M;Marini A;King LDW;Morris FC;Anderson G;Toellner KM;Henderson IR;López-Macías C;MacLennan CA;Cunningham AF
• 通讯作者: Cunningham AF

Soluble flagellin coimmunization attenuates Th1 priming to Salmonella and clearance by modulating dendritic cell activation and cytokine production.

• DOI: 10.1002/eji.201545564
• 发表时间: 2015-08
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Flores-Langarica A;Bobat S;Marshall JL;Yam-Puc JC;Cook CN;Serre K;Kingsley RA;Flores-Romo L;Uematsu S;Akira S;Henderson IR;Toellner KM;Cunningham AF
• 通讯作者: Cunningham AF

Inflammation-induced formation of fat-associated lymphoid clusters.

• DOI: 10.1038/ni.3215
• 发表时间: 2015-08
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Bénézech C;Luu NT;Walker JA;Kruglov AA;Loo Y;Nakamura K;Zhang Y;Nayar S;Jones LH;Flores-Langarica A;McIntosh A;Marshall J;Barone F;Besra G;Miles K;Allen JE;Gray M;Kollias G;Cunningham AF;Withers DR;Toellner KM;Jones ND;Veldhoen M;Nedospasov SA;McKenzie ANJ;Caamaño JH
• 通讯作者: Caamaño JH

Vi polysaccharide and conjugated vaccines afford similar early, IgM or IgG-independent control of infection but boosting with conjugated Vi vaccines sustains the efficacy of immune responses.

• DOI: 10.3389/fimmu.2023.1139329
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3