Dynamics of human T cell memory in blood and secondary lymphoid tissue in shaping vaccine induced immunity in ageing

血液和次级淋巴组织中人类 T 细胞记忆的动态在塑造疫苗诱导的衰老免疫力中的作用

• 批准号: MR/W024977/1
• 负责人: Katrina Pollock
• 金额: $ 202.78万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW024977%2F1
• 关键词: Dynamics; human; cell; memory; blood

Vaccines protect by training the immune system to retain memory of an infection. This is made up of different kinds of cells which can retain information, like bits in a computer software system. This is called immune memory. It is this feature which allows us to be protected after vaccination if we encounter an infection. We do not fully understand the processes involved. One very important type of T cell interacts with B cells to help them make antibodies. These interactions happen in specialised tissues called lymph nodes. These are small kidney-shaped organs found together in clusters in certain areas such as the underarm. It is here that T cells and B cells meet the vaccine or parts of the vaccine and as a result, the cells respond, change and multiply. In older people, we know that the processes of immune priming, maintaining immune memory and recalling it may all happen differently, perhaps more slowly, but we don't know precisely why. One possibility is that T cells respond differently in older people. Vaccines for older people often need a high dose or an extra activating component. Although lymph nodes are important, they have not been well studied in humans. This is because taking a lymph node sample requires different skills from taking blood and these have not previously been invested in. A clinician who is skilled in ultrasound-guided needle biopsy, is needed. This means that we are missing key information in understanding how vaccines work, and how we might design them better in different circumstances; for older people for example, or to tackle highly complex infections that rapidly change such as HIV, flu and SARS-CoV-2. This Fellowship aims to change that. Not just for the duration of this project but for the future of vaccine science. Firstly, I will develop bedside imaging to determine which lymph nodes are responding to the vaccine and which are not. At present this is sometimes possible with greyscale ultrasound but the results are not always reliable, or with PET/CT but this involves a dose of radiation. I believe we can do this more frequently and in more people using harmless ultrasound. Volunteers will be vaccinated with a vaccine against influenza and attend for an imaging appointment on multiple days before and after vaccination. Each time they attend they will have a scan to see the size and blood flow in the lymph nodes near to the site of vaccination. This will determine the best site and best day on which to take a sample using these types of vaccines. Secondly, I will use the ultrasound to guide a fine needle aspiration (USFNA) biopsy to take a sample of the lymph node before and after vaccination with influenza vaccine. I will also ask volunteers to give a sample of the blood at the same time. Samples from lymph nodes on the same side and opposite (control) side can be taken. The cells will be stained and measured using a machine called a flow cytometer so that I can determine which are T cells, what type of T cells, what they are responding to and whether they are growing in number (in cell cycle). I will compare this in the blood and in the lymph node. Thirdly, I will measure how individual T cells are responding to vaccination by testing the ribonucleic acid (RNA) that they are producing. This will indicate in detail how different types of T cells respond to the vaccine. To understand how age might affect the immune response, I will ask people of different ages to participate. My vision is to generate a picture of how T cells respond to vaccines in lymph nodes, and to demonstrate how, and why, this changes with age. This will provide new insight for the future of vaccine design.

疫苗通过训练免疫系统保持对感染的记忆来保护病毒。这是由可以保存信息的不同类型的单元组成的，就像计算机软件系统中的位一样。这被称为免疫记忆。正是这一特征使我们在接种疫苗后，如果遇到感染，可以得到保护。我们并不完全了解所涉及的过程。一种非常重要的T细胞与B细胞相互作用，帮助它们制造抗体。这些相互作用发生在称为淋巴结的特殊组织中。这些小的肾脏形状的器官聚集在一起，在某些区域，如腋下。正是在这里，T细胞和B细胞与疫苗或部分疫苗相遇，结果，细胞做出反应、变化和繁殖。在老年人身上，我们知道免疫启动、保持免疫记忆和回忆记忆的过程可能都不同，可能会更慢，但我们不知道确切的原因。一种可能性是，T细胞对老年人的反应不同。老年人的疫苗通常需要高剂量或额外的激活成分。虽然淋巴结很重要，但在人类身上还没有得到很好的研究。这是因为采集淋巴结样本需要与采集血液不同的技术，而这些技术以前没有投入过。需要一位精通超声引导针吸活组织检查的临床医生。这意味着我们在理解疫苗是如何工作的，以及我们如何在不同的情况下设计出更好的疫苗方面缺乏关键信息；例如，针对老年人，或者应对艾滋病毒、流感和SARS-CoV-2等快速变化的高度复杂的感染。本次联谊会旨在改变这一点。不仅是在这个项目的持续时间内，而且在疫苗科学的未来。首先，我将开发床边成像，以确定哪些淋巴结对疫苗有反应，哪些没有。目前，灰阶超声有时可以做到这一点，但结果并不总是可靠的，或者使用PET/CT，但这涉及到辐射剂量。我相信我们可以更频繁地在更多的人身上使用无害的超声波。志愿者将接种流感疫苗，并在接种疫苗前和接种后的多天内进行成像预约。每次他们参加时，他们都会进行扫描，看看疫苗接种地点附近的淋巴结的大小和血流情况。这将确定使用这些类型的疫苗进行采样的最佳地点和最佳日期。其次，我将使用超声波引导细针抽吸(USFNA)活检，在接种流感疫苗之前和之后采集淋巴样本。我还会要求志愿者同时提供血液样本。可从同侧和对侧(对照)的淋巴结中采集样本。这些细胞将被染色，并使用一种名为流式细胞仪的机器进行测量，这样我就可以确定哪些是T细胞，什么类型的T细胞，它们对什么反应，以及它们是否在数量上(在细胞周期中)增长。我会在血液和淋巴结中进行比较。第三，我将通过测试T细胞产生的核糖核酸(RNA)来衡量单个T细胞对疫苗接种的反应。这将详细说明不同类型的T细胞对疫苗的反应。为了了解年龄如何影响免疫反应，我将邀请不同年龄的人参与其中。我的愿景是制作一张T细胞如何对淋巴结中的疫苗做出反应的图片，并展示这种反应如何以及为什么会随着年龄的变化而变化。这将为疫苗设计的未来提供新的见解。

项目成果

Comparison of blood and lymph node cells after intramuscular injection with HIV envelope immunogens.

• DOI: 10.3389/fimmu.2022.991509
• 发表时间: 2022
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Day, Suzanne;Kaur, Charandeep;Cheeseman, Hannah M.;de Groot, Emily;McFarlane, Leon R.;Tanaka, Maniola;Coelho, Sofia;Cole, Tom;Lemm, Nana-Marie;Lim, Adrian;Sanders, Rogier W.;Asquith, Becca;Shattock, Robin J.;Pollock, Katrina M.
• 通讯作者: Pollock, Katrina M.

Enhanced immune responses following heterologous vaccination with self-amplifying RNA and mRNA COVID-19 vaccines.

• DOI: 10.1371/journal.ppat.1010885
• 发表时间: 2022-10
• 期刊: PLOS PATHOGENS
• 影响因子: 6.7
• 作者: Elliott, Tamara;Cheeseman, Hannah M.;Evans, Abbey B.;Day, Suzanne;McFarlane, Leon R.;O'Hara, Jessica;Kalyan, Mohini;Amini, Fahimah;Cole, Tom;Winston, Alan;Fidler, Sarah;Pollock, Katrina M.;Harker, James A.;Shattock, Robin J.
• 通讯作者: Shattock, Robin J.

Booster Vaccination Against SARS-CoV-2 Induces Potent Immune Responses in People With Human Immunodeficiency Virus.

• DOI: 10.1093/cid/ciac796
• 发表时间: 2023-01-13
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study.

• DOI: 10.1016/s2468-1253(22)00274-6
• 发表时间: 2022-11
• 期刊: LANCET GASTROENTEROLOGY & HEPATOLOGY
• 影响因子: 35.7
• 作者: Alexander, James L.;Liu, Zhigang;Sandoval, Diana Munoz;Reynolds, Catherine;Ibraheim, Hajir;Anandabaskaran, Sulak;Saifuddin, Aamir;Seoane, Rocio Castro;Anand, Nikhil;Nice, Rachel;Bewshea, Claire;D'Mello, Andrea;Constable, Laura;Jones, Gareth R.;Balarajah, Sharmili;Fiorentino, Francesca;Sebastian, Shaji;Irving, Peter M.;Hicks, Lucy C.;Williams, Horace R. T.;Kent, Alexandra J.;Linger, Rachel;Parkes, Miles;Kok, Klaartje;Patel, Kamal V.;Teare, Julian P.;Altmann, Daniel M.;Goodhand, James R.;Hart, Ailsa L.;Lees, Charlie W.;Boyton, Rosemary J.;Kennedy, Nicholas A.;Ahmad, Tariq;Powell, Nick
• 通讯作者: Powell, Nick

Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study.

• DOI: 10.1016/s2468-1253(22)00389-2
• 发表时间: 2023-02
• 期刊: LANCET GASTROENTEROLOGY & HEPATOLOGY
• 影响因子: 35.7
• 作者: Liu, Zhigang;Le, Kaixing;Zhou, Xin;Alexander, James L.;Lin, Simeng;Bewshea, Claire;Chanchlani, Neil;Nice, Rachel;McDonald, Timothy J.;Lamb, Christopher A.;Sebastian, Shaji;Kok, Klaartje;Lees, Charlie W.;Hart, Ailsa L.;Pollok, Richard C.;Boyton, Rosemary J.;Altmann, Daniel M.;Pollock, Katrina M.;Goodhand, James R.;Kennedy, Nicholas A.;Ahmad, Tariq;Powell, Nick
• 通讯作者: Powell, Nick