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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.