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(新冠肺炎补充研究) 在快速传播的疾病暴发期间(如目前的新冠肺炎大流行)，快速诱导 通过接种疫苗进行群体免疫是至关重要的。目前在中国有许多SARS-CoV2候选疫苗 临床发展的不同阶段，旨在诱导强大的多模式保护性免疫，包括 既有长寿抗体也有记忆T细胞。然而，我们几乎无法控制保护的速度 免疫后可建立免疫力。至少，疫苗诱导的T细胞需要 初始免疫后约20-30天的抗原休息期，以有效下调其效应器 编程并转换成静止的、功能强大的、长寿命的记忆细胞，稳定在病原体的入口 进入。如果疫苗诱导的T细胞在强制休息期间再次暴露于抗原--这是可能发生的 在暴发期间暴露于强毒病原体的情况下--数量、质量和全面保护 免疫记忆的功效受到严重威胁。因此，缩短免疫记忆的窗口 发展是疫苗接种过程中的一个关键目标，在大流行期间建立 加快对一线医疗保健和基本服务提供者的保护，并加快 总人口将加速恢复正常和经济增长。 在本行政副刊中，我们将评估候选免疫调节策略，以加速和 通过促进Treg辅助效应对SARS-CoV2的免疫增强疫苗诱导的保护性T细胞记忆 内存转换。这项工作是基于我们的研究确立了Tregs在促进 通过CTLA4实现效应到记忆的转换，CTLA4是一种在树突状细胞上高表达的抑制分子 (在所有免疫细胞中)(免疫，2015)。重要的是，单独以反式给药的可溶性CTLA4能够 充分补充Tregs在记忆分化中的作用，加速保护性细胞的形成 通过促进效应器向记忆转换所必需的代谢开关来抗病毒免疫。这些 病毒免疫模型的概念验证研究(在过去的R21和亲本R01的支持下进行 Awards)为加强免疫后SARS-CoV2特异性免疫记忆奠定了坚实的基础 与SARS-CoV2候选疫苗在临床前小鼠模型中的作用。这些研究代表了一种自然的 亲本R01的翻译延伸侧重于Treg依赖的机制和分子细节 在病毒感染模型中通过CTLA4增强记忆。重要的是，CTLA4-Ig是FDA批准的阶段 III药物已准备好用于临床翻译。因此，对我们快速建立羊群的能力有直接影响 预计对SARS-CoV2具有免疫力。除了解决当前新冠肺炎的紧迫性外，这些 研究还涉及其他流行病和我国国防部队紧急接种疫苗的情况。 快速部署到疾病流行地区。