Mechanisms of T Cell Memory Quiescence

T 细胞记忆静止机制

基本信息

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
项目类别：
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

项目摘要

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）在快速传播的疾病爆发期间（例如当前的 COVID-19 大流行），快速诱导通过疫苗接种实现群体免疫至关重要，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保护性免疫，包括然而，我们无法控制长寿命抗体和记忆 T 细胞的保护速度。免疫后可能会建立免疫力，疫苗诱导的 T 细胞至少需要初次免疫后约 20-30 天的抗原休息期，以有效下调其效应子编程并转化为静止的、功能强大的、寿命长的记忆细胞，处于病原体的入口处如果疫苗诱导的 T 细胞在这个强制休息期间重新暴露于抗原——这可能会发生。如果在爆发期间接触剧毒病原体——数量、质量和总体防护因此，免疫记忆的功效会受到显着损害。发展是疫苗接种期间的一个关键目标，在大流行期间具有重要意义加快对一线医疗保健和基本服务提供者的保护，并加快群体免疫广大民众呼吁尽快恢复正常和经济增长。在本行政补充中，我们将评估候选免疫调节策略，以加速和通过促进 Treg 辅助效应器来增强疫苗诱导的对 SARS-CoV2 的保护性 T 细胞记忆这项工作基于我们的研究，确定了 Tregs 在促进记忆转换方面的关键作用。通过 CTLA4（一种在 Tregs 上表达最高的抑制分子）实现效应器到记忆的转换（在所有免疫细胞中）（Immunity，2015）重要的是，反式施用的可溶性 CTLA4 能够单独发挥作用。充分补充Tregs在记忆分化中的功能，加速保护性细胞的形成通过促进效应器到记忆转换所需的代谢转换来抗病毒免疫。病毒免疫模型的概念验证研究（在过去的 R21 和母公司 R01 的支持下进行）奖）为增强免疫后 SARS-CoV2 特异性免疫记忆奠定坚实的基础这些研究代表了一种自然的临床前小鼠模型中的候选 SARS-CoV2 疫苗。母体 R01 的翻译延伸，重点关注 Treg 依赖性的机制和分子细节通过 CTLA4 在病毒感染模型中增强记忆重要的是，CTLA4-Ig 已获得 FDA 批准。 III 药物 - 准备进行临床转化因此，直接影响我们快速建立群体的能力。除了解决当前的 COVID-19 紧急情况外，这些药物还有望获得针对 SARS-CoV2 的免疫力。研究还涉及其他流行病以及我们国防军紧急接种疫苗的情况快速部署到疾病流行地区。