Browsing by Subject "Dendritic cells"

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    Adenosine regulation of danger signaling
    (2017-07) Akdemir, İmran
    Metabolic and immune related activities converge as main triggers of adenosine accumulation in extracellular space. Adenosine by engaging adenosine A2A and A2B receptors strongly suppresses innate and adaptive immune responses. Although adenosine receptors are being targeted in preclinical and clinical studies, how different danger signals are regulated by adenosine is poorly understood. Here we showed that adenosine receptor stimulation strongly inhibited inflammatory responses while sparing Type-I interferon responses downstream of different danger signals in dendritic cells and macrophages. Mechanistically, danger signals associated with MyD88-dependent inflammatory pathways such as LPS and CpG but not the danger signals associated with IRF3/Type-I interferon pathways such as pA:U and cGAMP increase the expression of adenosine A2A and A2B receptors. Expression of anti-inflammatory NR4A1 was increased after adenosine receptor stimulation in the presence of TLR ligands known to activate MyD88 pathway but not in the presence of cGAMP and pA:U. Overall these results indicate that there is a differential modulation of danger signaling by adenosine rather than overall suppression. Our results have important implications for developing combinatorial approaches to target adenosine and danger signaling pathways to cure immune-related diseases.
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    Antigenic GM3 lactone mimetic molecule integrated mannosylated glycopeptide nanofibers for the activation and maturation of dendritic cells
    (American Chemical Society, 2017) Gunay, Gokhan; Ekiz, Melis Sardan; Ferhati, X.; Richichi, B.; Nativi, C.; Tekinay, Ayse B.; Güler, Mustafa O.
    The ability of dendritic cells to coordinate innate and adaptive immune responses makes them essential targets for vaccination strategies. Presentation of specific antigens by dendritic cells is required for the activation of the immune system against many pathogens and tumors, and nanoscale materials can be functionalized for active targeting of dendritic cells. In this work, we integrated an immunogenic, carbohydrate melanoma-associated antigen-mimetic GM3-lactone molecule into mannosylated peptide amphiphile nanofibers to target dendritic cells through DC-SIGN receptor. Based on morphological and functional analyses, when dendritic cells were treated with peptide nanofiber carriers, they showed significant increase in antigen internalization and a corresponding increase in the surface expression of the activation and maturation markers CD86, CD83 and HLA-DR, in addition to exhibiting a general morphology consistent with dendritic cell maturation. These results indicate that mannosylated peptide amphiphile nanofiber carriers are promising candidates to target dendritic cells for antigen delivery. © 2017 American Chemical Society.
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    Eliciting immune response by using nanostructures
    (2017-06) Günay, Gökhan
    The ability of dendritic cells to coordinate innate and adaptive immune responses makes them essential targets for vaccination strategies. Presentation of specific antigens by dendritic cells is required for the activation of the immune system against many pathogens and cancer, and nanoscale materials can be functionalized for active targeting of dendritic cells. In this work, we integrated an immunogenic, carbohydrate melanoma-associated antigen-mimetic GM3-lactone molecule into mannosylated peptide amphiphile nanofibers to target dendritic cells through DC-SIGN receptor. Based on morphological and functional analyses, when dendritic cells were treated with peptide nanofiber carriers, they showed significant increase in antigen internalization and a corresponding increase in the surface expression of the activation and maturation markers CD86, CD83 and HLA-DR, in addition to exhibiting a general morphology consistent with dendritic cell maturation. These results indicate that mannosylated peptide amphiphile nanofiber carriers are promising candidates to target dendritic cells for antigen delivery. Overall these structures are proven to be effective in terms of dendritic cell activation and maturation and hold high potential to be used with a variety of antigens for different immunotherapy purposes.
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    Induction of potent protection against acute and latent herpes simplex virus infection in mice vaccinated with dendritic cells
    (2013) Ghasemi, M.; Erturk, M.; Buruk, K.; Sonmez, M.
    Background aims. Dendritic cells (DCs) are the most potent antigen presenting cells of the immune system and have been under intense study with regard to their use in immunotherapy against cancer and infectious disease agents. In the present study, DCs were employed to assess their value in protection against live virus challenge in an experimental model using lethal and latent herpes simplex virus (HSV) infection in Balb/c mice. Methods. DCs obtained ex vivo in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 were loaded with HSV-1 proteins (DC/HSV-1 vaccine). Groups of mice were vaccinated twice, 7 days apart, via subcutaneous, intraperitoneal or intramuscular routes with DC/HSV-1 and with mock (DC without virus protein) and positive (alum adjuvanted HSV-1 proteins [HSV-1/ALH]) control vaccines. After measuring anti-HSV-1 antibody levels in blood samples, mice were given live HSV-1 intraperitoneally or via ear pinna to assess the protection level of the vaccines with respect to lethal or latent infection challenge. Results. Intramuscular, but not subcutaneous or intraperitoneal, administration of DC/HSV-1 vaccine provided complete protection against lethal challenge and establishment of latent infection as assessed by death and virus recovery from the trigeminal ganglia. It was also shown that the immunity was not associated with antibody production because DC/HSV-1 vaccine, as opposed to HSV-1/ALH vaccine, produced very little, if any, HSV-1-specific antibody. Conclusions. Overall, our results may have some impact on the design of vaccines against genital HSV as well as chronic viral infections such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus. © 2013, International Society for Cellular Therapy.
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    Molecular mechanism for adenosine regulation of dendritic cells
    (2017-05) Kayhan, Merve
    Cell death, inflammation or other cellular stress factors cause accumulation of adenosine in the extracellular space. Adenosine has immunosuppressive effects on antigen presenting cells. However, molecular mechanisms for adenosine regulation of dendritic cells are poorly understood. Here we showed that adenosine receptor signaling promotes an antiinflammatory dendritic cell phenotype. While adenosine receptor signaling increased intracellular cAMP levels, phosphoactivation of major inflammatory pathways such as MAPKs, NF-κB and IRF3 were not affected. Adenosine’s effects were phenocopied by cAMP. Specific cAMP analogs for EPAC and PKA pathways indicated that adenosine activates both intracellular cAMP receptors to inhibit dendritic cell activation. Antiinflammatory cFOS and NR4A receptor family expressions were increased by adenosine or EPAC and PKA specific cAMP analogs. Furthermore, T cells incubated with the medium of dendritic cells, which prestimulated with adenosine receptor agonist and PKAEPAC specific cAMP analogs, produced less IFNγ. Overall our data suggest that dendritic cells are regulated by adenosine through both PKA and EPAC pathways and increased the expression of NR4A nuclear orphan receptors and cFOS. Our findings suggest that for effective targeting of adenosine or other cAMP-inducing receptors both PKA and EPAC are important to modulate immune responses