Combination Adjuvants to Activate Human Dendritic Cell Subsets and B Cells

激活人树突状细胞亚群和 B 细胞的组合佐剂

基本信息

批准号：
9890987
负责人：
Jacques F Banchereau
金额：
$ 60.5万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890987
关键词：
ATAC-seq Accounting Adjuvant Agonist Antibodies Antibody Response Area B-Lymphocytes Biological Assay CD34 gene CD4 Positive T Lymphocytes CRISPR/Cas technology Cells Collaborations Communicable Diseases Computational Biology Cytometry Dendritic Cell Vaccine Dendritic Cells Elderly Elements Engineering Engraftment Epigenetic Process Event Exposure to FDA approved Flow Cytometry Genes Genetic Enhancer Element Genetic Transcription Genomics Goals Helper-Inducer T-Lymphocyte Human Human Engineering Humoral Immunities IgA1 IgA2 IgE IgG1 IgG3 Immune Immune response Immune system Immunity Immunobiology Immunocompromised Host Immunodeficient Mouse Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunologic Receptors In Vitro Inactivated Vaccines Individual Industry Influenza Interferon Type II Interleukin-13 Interleukin-17 Interleukin-4 Investigation Lead Metabolic Methods Molecular Morbidity - disease rate Mus Outcome Output Pathway interactions Pattern Phosphorylation Plasma Cells Population Proteomics Public Health RNA Recombinants Research Research Personnel STING agonists Safety Selection Criteria Sendai virus Signal Transduction Site Subunit Vaccines System TLR4 gene TLR7 gene Technology Testing The Jackson Laboratory Vaccination Vaccine Antigen Vaccines base bioinformatics infrastructure computer infrastructure design epigenome epigenomics genome editing genomic data humanized mouse immunogenicity immunosuppressed in vivo innovation insight knock-down metabolomics mortality mouse development mouse model novel vaccines pathogen prevent programs promoter protein expression public health relevance receptor reconstitution response side effect small hairpin RNA synergism tool transcriptome transcriptomics vaccine development vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Vaccination is the most effective method for preventing infectious diseases. Many current vaccines are "inactivated" or "subunit" vaccines composed of purified or recombinant pathogen components to which an adjuvant is often added to increase the magnitude of antibody responses. However, subunit vaccines formulated with current FDA-approved adjuvants do not sufficiently boost immunity in some populations, particularly immunocompromised and elderly subjects. Numerous adjuvants have been discovered in recent years and show enhanced immunogenicity as single agents; however, little is known about the activity of their combination, their safety, their efficacy and their mechanisms of action. Responses to vaccination and adjuvants involve dendritic cells (DCs), which capture and present vaccine antigens thereby facilitating the differentiation of follicular helper T cells (Tfh) and B cells and subsequent humoral immunity. Therefore, we propose to examine the molecular mechanisms and functional outputs of human DC subsets exposed to combination adjuvants ex vivo and in vivo. The focus on human DCs is essential given the substantial differences in innate immune receptor distribution and function between the mouse and the human. Our goal is to select a combination adjuvant using functional assays, followed by in-depth investigation of molecular pathways accounting for enhanced immunogenicity. Our collaboration with industry will enable the transition of the selected combination adjuvant to further studies of human vaccination. Our Specific Aims are built towards this goal. Thus, first we will screen adjuvant combinations by assessing the capacity of adjuvant-activated human DC subsets to skew the differentiation of naïve CD4+T cells into Tfh cells that secrete IL-21 and induce B cells to produce IgG and IgA antibodies (Aim 1). Promising combinations will be further studied in DCs using validated, sensitive and high-throughput transcriptomic epigenomic, proteomic and metabolomic methods, and by functional knockdown in vitro, to determine the underlying molecular pathways of adjuvant efficacy (Aim 2). We will then validate the identified molecular pathways through functional knockdown studies in vivo using humanized mice carrying a functionally reconstituted human immune system, which will also enable the examination of possible side effects (Aim 3). The proposed research program will leverage cutting-edge epigenetic (ATAC-seq), transcriptional, gene editing (CRISPR/Cas9) and metabolomic technologies; innovative humanized mouse models; a powerful computational and bioinformatics infrastructure at The Jackson Laboratory; and the complementary expertise of a dynamic team of investigators. Our deliverable is a combination adjuvant for enhanced humoral immunity and molecular pathways that are essential for its efficacy.

描述（申请人提供）：疫苗接种是预防传染病最有效的方法，目前许多疫苗是由纯化或重组的病原体成分组成的“灭活”或“亚单位”疫苗，其中通常添加佐剂以增加抗体的强度。然而，用目前 FDA 批准的佐剂配制的亚单位疫苗并不能充分增强某些人群的免疫力，特别是免疫功能低下和老年受试者。近年来，已经发现了许多佐剂并显示出增强作用。作为单一药物的免疫原性；然而，对其组合的活性、安全性、功效和机制知之甚少。对疫苗接种和佐剂的反应涉及树突状细胞 (DC)，树突状细胞捕获并呈递疫苗抗原，从而促进滤泡辅助 T 细胞 (Tfh) 和 B 细胞的分化以及随后的体液免疫。考虑到小鼠和人类之间先天免疫受体分布和功能的显着差异，对人类 DC 的关注至关重要。使用功能测定选择组合佐剂，然后深入研究增强免疫原性的分子途径，将使所选组合佐剂过渡到人类疫苗接种的进一步研究。因此，首先我们将通过评估佐剂激活的人 DC 亚群将初始 CD4+T 细胞分化为分泌 IL-21 并诱导 B 细胞分化的 Tfh 细胞的能力来筛选佐剂组合。产生 IgG 和 IgA 抗体（目标 1）将使用经过验证的、灵敏的和高通量的转录组学表观基因组学、蛋白质组学和代谢组学方法，并通过体外功能敲低，在 DC 中进一步研究有前途的组合，以确定佐剂功效的潜在分子途径。（目标 2）然后，我们将使用携带功能重建的人类免疫系统的人源化小鼠，通过体内功能敲低研究来验证已确定的分子途径，这也将能够检查可能的一面。拟议的研究计划将利用尖端的表观遗传学 (ATAC-seq)、转录、基因编辑 (CRISPR/Cas9) 和代谢组学技术；杰克逊实验室强大的计算和生物信息学基础设施；以及充满活力的研究团队的互补专业知识，我们的成果是增强体液免疫和对其功效至关重要的分子途径的组合佐剂。