Mechanisms of T Cell Memory Quiescence

T 细胞记忆静止机制

• 批准号: 10265656
• 负责人: Surojit Sarkar
• 金额: $ 51.33万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265656
• 关键词: 2019-nCoV; ACE2; Acquired Immunodeficiency Syndrome; Address; Administrative Supplement; Antibodies; Antigens; Area; Award; B-Lymphocytes; Bacterial Infections; Biological; CD28 gene; COVID-19; COVID-19 pandemic; COVID-19 vaccine; CTLA4 gene; CTLA4-Ig; Cells; Cellular Immunity; Centers for Disease Control and Prevention (U.S.); Childhood; Clinical; Clinical Trials; Communicable Diseases; Consensus; Development; Disease Outbreaks; Drug usage; Economic Burden; Economics; Endemic Diseases; Engineering; Epidemic; Etiology; Evaluation; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; FDA approved; Foundations; Future; General Population; Goals; Growth; Healthcare; Hepatitis C virus; Herd Immunity; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunologic Memory; Lead; Location; Longevity; Lung; Lymphoid Tissue; Malaria; Mediating; Memory; Metabolic; Modeling; Molecular; Normalcy; Nucleoproteins; Outcome; Parents; Pharmaceutical Preparations; Phase; Play; Property; Proteins; Public Health; Recovery; Regulatory T-Lymphocyte; Research; Rest; Rheumatoid Arthritis; Role; SARS-CoV-2 spike protein; Severe Acute Respiratory Syndrome; Signal Transduction; Speed; Structural Protein; T memory cell; T-Lymphocyte; Time; Transgenic Mice; Travel; Tuberculosis; United States National Institutes of Health; Vaccination; Vaccine Design; Vaccines; Vaccinia virus; Viral; Virulent; Virus Diseases; Work; antigen-specific T cells; antiviral immunity; base; clinical development; clinical translation; drug repurposing; drug testing; expression vector; fight against; immunomodulatory strategy; inhibitor/antagonist; mouse model; multimodality; neutralizing antibody; pandemic disease; pathogen; pre-clinical; programs; protective efficacy; protein expression; repository; response; service providers; tool; vaccine candidate; vaccine-induced immunity; vector

ABSTRACT (COVID-19 SUPPLEMENTAL RESEARCH) During fast-spreading disease outbreaks (such as the present COVID-19 pandemic), quick induction of herd immunity through vaccination is critical. Currently there are many SARS-CoV2 candidate vaccines in various stages of clinical development, aimed at inducing robust multimodal protective immunity comprising both long-lived antibody and memory T cells. However, we have little control over how quickly protective immunity may be established following immunization. At the very minimum, vaccine-induced T cells require a period of ~20-30 days of antigenic rest after initial immunization to effectively downregulate their effector program and convert into quiescent, functionally potent, long-lived memory cells poised at portals of pathogen entry. If vaccine-induced T cells are re-exposed to antigen during this mandatory rest period – as might occur in case of exposure to virulent pathogen during an outbreak – the quantity, quality and overall protective efficacy of immune memory are significantly jeopardized. Hence, shortening the window of immune memory development is a key goal during vaccination, and is of high significance during pandemics to establish accelerated protection in frontline healthcare and essential service providers, and speed up herd immunity in the general population for expedited return to normalcy and economic growth. In this administrative supplement, we will evaluate candidate immunomodulatory strategies to accelerate and enhance vaccine-induced protective T cell memory to SARS-CoV2 by facilitating Treg-aided effector-to- memory conversion. This work is based on our studies establishing a critical role of Tregs in promoting effector-to-memory conversion through CTLA4, an inhibitory molecule most highly expressed on Tregs (amongst all immune cells) (Immunity, 2015). Importantly, soluble CTLA4 administered in trans, is alone able to fully supplement the function of Tregs in memory differentiation, and accelerates the formation of protective anti-viral immunity by promoting the metabolic switch necessary for effector-to-memory conversion. These proof-of-concept studies in models of viral immunity (conducted under the aegis of past R21, and parent R01 awards) lay a strong foundation for enhancing SARS-CoV2-specific immune memory following immunization with candidate SARS-CoV2 vaccine in preclinical murine model. These studies represent a natural translational extension of the parent R01 focused on mechanistic and molecular details of Treg-dependent memory enhancement through CTLA4 in model viral infections. Importantly, CTLA4-Ig is FDA-approved Phase III drug – ready for clinical translation. Therefore, immediate impact on our ability to quickly establish herd immunity against SARS-CoV2 is expected. In addition to addressing the current COVID-19 exigency, these studies are also relevant to other pandemics and situations of urgent vaccination of our defense troops for quick deployment to disease endemic areas.

摘要（COVID-19补充研究） 在快速发展的疾病暴发（例如目前的Covid-19大流行）中，快速诱导 通过疫苗的牛群免疫学至关重要。目前有许多SARS-COV2候选疫苗 临床开发的各个阶段，旨在诱导强大的多模式防护性完成 长寿命抗体和记忆T细胞。但是，我们几乎无法控制多快的保护 免疫后可以建立免疫力。至少，疫苗诱导的T细胞需要 初始免疫后约20-30天的抗原休息时间有效下调其效应器 编程并转化为静止的，功能潜在的，长寿命的记忆细胞在病原体的门户中毒 入口。如果在此强制性休息期间将疫苗诱导的T细胞重新暴露于抗原 - 可能发生 如果在暴发期间暴露于有毒病原体的情况下 - 数量，质量和总体保护 免疫记忆的功效显着危害。因此，缩短免疫记忆的窗口 开发是疫苗接种期间的关键目标，并且在大流行期间具有很高的意义 一线医疗保健和基本服务提供商的加速保护，并加快群群免疫力 加快正常和经济增长的加急人口。 在这种行政补充中，我们将评估候选免疫调节策略以加速和 通过支持Treg辅助效应器到 - 内存转换。这项工作基于我们的研究，确立了Treg在促进中的关键作用 通过CTLA4的效应子到记忆转换，这是一种在Treg上最高表达的抑制性分子 （在所有免疫细胞中）（免疫，2015年）。重要的是，在trans中施用的可溶性ctla4是一个人 充分补充Treg在记忆分化中的功能，并加速保护性 抗病毒免疫通过促进效应器到记忆转换所需的代谢开关。这些 病毒免疫模型的概念验证研究（根据过去R21的宙斯盾和父级R01进行 奖项）为增强免疫后增强SARS-COV2特异性免疫记忆的坚实基础 临床前鼠模型中的候选SARS-COV2疫苗。这些研究代表了自然 母体R01的翻译扩展，重点依赖于Treg依赖性的机械和分子细节 模型病毒感染中通过CTLA4增强记忆力。重要的是，CTLA4-Ig是FDA批准的阶段 III药物 - 准备进行临床翻译。因此，立即影响我们快速建立牛群的能力 预计对SARS-COV2的免疫力将有望。除了解决当前的Covid-19紧急情况之外，这些 研究还与我们国防部队紧急疫苗接种的其他大流行有关 快速部署到疾病内在区域。