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Sorted B cells from mice treated with MPL and/or R837

ABSTRACT: Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence suggests that activate dendritic cells (DCs) via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates DCs via multiple TLRs to stimulate pro-inflammatory cytokines. Triggering specific combinations of TLRs in DCs can induce synergistic production of cytokines, which results in enhanced T cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that programs such antibody responses remains a major challenge in vaccinology. We demonstrated that immunization of mice with synthetic nanoparticles containing antigens plus Toll-like receptor (TLR) ligands 4 (MPL) + 7 (R837) induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with a single TLR ligand. To determine whether there was any early programming of B cells, we isolated isotype switched, TCRbeta-CD11b-CD19+IgD-IgG+ B cells by FACS at 7 days post immunization with nanoparticles containing various adjuvants plus OVA, and performed microarray analyses to assess their molecular signatures.

ORGANISM(S): Mus musculus

PROVIDER: GSE25677 | GEO | 2010/12/01

SECONDARY ACCESSION(S): PRJNA133875

REPOSITORIES: GEO

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Sorted B cells from mice treated with MPL and/or R837

Project description:Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence suggests that activate dendritic cells (DCs) via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates DCs via multiple TLRs to stimulate pro-inflammatory cytokines. Triggering specific combinations of TLRs in DCs can induce synergistic production of cytokines, which results in enhanced T cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that programs such antibody responses remains a major challenge in vaccinology. We demonstrated that immunization of mice with synthetic nanoparticles containing antigens plus Toll-like receptor (TLR) ligands 4 (MPL) + 7 (R837) induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with a single TLR ligand. To determine whether there was any early programming of B cells, we isolated isotype switched, TCRbeta-CD11b-CD19+IgD-IgG+ B cells by FACS at 7 days post immunization with nanoparticles containing various adjuvants plus OVA, and performed microarray analyses to assess their molecular signatures. Two independent sets of samples at day 7 post-treatment were used in our analyses. Each set is comprised by B-cells from mice treated with MPL + R837 or from those treated with either individual MPL or R837 alone.

2010-12-01 | E-GEOD-25677 | biostudies-arrayexpress

Transcription profiling of human dendritic cells to identify a combinatorial code by which DCs discriminate pathogens and provide (suggest) a rationale to design adjuvants for TH1 responses.

Project description:Toll like receptors (TLRs) sense microbial products and initiate adaptive immune responses by activating dendritic cells (DCs). Since pathogens may contain several agonists we asked whether different TLRs may synergize in DC activation. We report that in human and mouse DC TLR3 or TLR4 potently synergize with TLR7, TLR8 or TLR9 in the induction of selected cytokine genes. Upon synergistic stimulation, IL-12, IL-23 and Delta-4 are induced at levels 50-100 fold higher than those induced by optimal concentrations of single agonists, leading to enhanced and sustained TH1 polarizing capacity. Using microarray analysis we show that only 1.5% of the transcripts induced by single TLR agonists are synergistically regulated by combinations of TLR4 and TLR8 agonists.. These results identify a combinatorial code by which DCs discriminate pathogens and provide (suggest) a rationale to design adjuvants for TH1 responses. Series_overall_design: 3 untreated, 3 treated with LPS at 2h, 3 treated with LPS at 8h, 3 treated with R848 at 2h, 3 treated with R848 at 8h, 3 treated with LPS + R848 at 2h, 3 treated with LPS + R848 at 8h

2007-09-14 | E-GEOD-2706 | biostudies-arrayexpress

Transcription profiling of human dendritic cells treated with lipopolysaccharides and R848

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Mapping myddosome components in human and murine macrophages.

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Immune response genes at the mRNA vaccine delivery sites and draining lymph nodes of rhesus macaques

Project description:mRNA vaccines are emerging as a powerful vaccine platform as they are well-tolerated and scalable. Modified non-replicating mRNA encoding Influenza hemagglutinin and encapsulated in lipid nanoparticles (LNP) induced robust antibody and CD4 T cell responses after intramuscular or intradermal delivery in rhesus macaques. We investigated the local innate immune responses modulating such vaccine-induced immunity at the sites of immunization (skeletal muscle and skin) and their draining lymph nodes (LNs). Rapid mobilization of antigen presenting cells was found at the LNP/mRNA-injection sites and LNs. Dendritic cells efficiently internalized the LNPs, translated the mRNA cargo and upregulated co-stimulatory molecules. In addition, several type I interferon-inducible genes were expressed at the immunization sites and draining LNs. The innate immune activation was transient and resulted in priming of antigen-specific CD4+ T cells exclusively in the vaccine-draining LNs. Collectively, mRNA-based vaccines induce type I interferon-polarized innate immunity and antigen production by antigen presenting cells, which resulted potent vaccine-specific responses.

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2018-11-16 | GSE112351 | GEO

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