Structure, mechanism and therapeutic utility of immunosuppressive oligonucleotides

Bayik, Defne; Gürsel, İhsan; Klinman, Dennis M.

doi:10.1016/j.phrs.2015.11.010

Cited by 29 publications

(40 citation statements)

References 104 publications

(173 reference statements)

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“…Our findings show that Sup ODN treatment significantly reduced the influx of inflammatory cells into the lungs and their production of pro-inflammatory cytokines, effects expected to reduce VILI (34). No clinically detectable adverse events (e.g., labored breathing, hemorrhage, infection, death) were observed in follow up periods ranging from 6-48 h, consistent with reports that Sup ODN are safe in rodents and non-human primates (18,22). Findings in this murine model support the further assessment of Sup ODN for the prevention/treatment of VILI.…”

Section: Discussionsupporting

confidence: 88%

“…Our group and others have studied a class of suppressive oligodeoxynucleotide (Sup ODN) that specifically inhibits inflammatory reactions (18,19). Sup ODN block macrophage activation and down-regulate the production of proinflammatory and Th1 cytokines (20,21) by inhibiting activation cascades utilizing STAT1, STAT3, STAT4 and the interferon-inducible protein AIM2 (19,(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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Suppressive oligonucleotides inhibit inflammation in a murine model of mechanical ventilator induced lung injury

Scheiermann¹,

Klinman²

2016

J. Thorac. Dis.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Suppressive oligonucleotides inhibit inflammation in a murine model of mechanical ventilator induced lung injury

Scheiermann¹,

Klinman²

2016

J. Thorac. Dis.

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“…The immune regulation using G-rich sequences is known to require relatively high ODN concentrations [65,66]. Usually, cellular uptake of ODNs is a crucial step for their interaction with a wide range of molecular targets because nucleic acids being polyanions cannot passively diffuse across cell membranes.…”

Section: Discussionmentioning

confidence: 99%

The Potential of Telomeric G-Quadruplexes Containing Modified Oligoguanosine Overhangs in Activation of Bacterial Phagocytosis and Leukotriene Synthesis in Human Neutrophils

et al. 2020

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Human neutrophils are the first line of defense against bacterial and viral infections. They eliminate pathogens through phagocytosis, which activate the 5-lipoxygenase (5-LOX) pathway resulting in synthesis of leukotrienes. Using HPLC analysis, flow cytometry, and other biochemical methods, we studied the effect of synthetic oligodeoxyribonucleotides (ODNs) able to fold into G-quadruplex structures on the main functions of neutrophils. Designed ODNs contained four human telomere TTAGGG repeats (G4) including those with phosphorothioate oligoguanosines attached to the end(s) of G-quadruplex core. Just modified analogues of G4 was shown to more actively than parent ODN penetrate into cells, improve phagocytosis of Salmonella typhimurium bacteria, affect 5-LOX activation, the cytosol calcium ion level, and the oxidative status of neutrophils. As evident from CD and UV spectroscopy data, the presence of oligoguanosines flanking G4 sequence leads to dramatic changes in G-quadruplex topology. While G4 folds into a single antiparallel structure, two main folded forms have been identified in solutions of modified ODNs: antiparallel and dominant, more stable parallel. Thus, both the secondary structure of ODNs and their ability to penetrate into the cytoplasm of cells are important for the activation of neutrophil cellular effects. Our results offer new clues for understanding the role of G-quadruplex ligands in regulation of integral cellular processes and for creating the antimicrobial agents of a new generation.

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“…The LNs enrichment was consistent with our previous observations, where lipid-modified ODNs bound endogenous albumin and transported to the LNs (19). In contrast, unmodified ODN quickly diffused into blood circulation due to its small molecular size and exhibited minimal LNs accumulation (19,27). Flow cytometry analysis of the cells in the LNs revealed that CD11c+ dendritic cells and F4/80+ macrophages were the major cells responsible for the uptake of lipo-A151.…”

Section: Discussionmentioning

confidence: 99%

Targeting Suppressive Oligonucleotide to Lymph Nodes Inhibits Toll-like Receptor-9-Mediated Activation of Adaptive Immunity

Jones

et al. 2018

Pharm Res

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Purpose This paper aims to investigate the immunoinhibitory properties of a lymph nodes-targeting suppressive oligonucleotide (ODN) for the potential treatment of autoimmune diseases or chronic inflammation. Methods Synthetic suppressive ODN engineered with an albumin-binding diacyl lipid at the 5’-terminal (lipo-ODN) was synthesized. In vitro and in vivo experiments were designed to compare the immune suppressive properties of lipo-ODN and unmodified ODN. Cellular uptake and distribution, inhibition of Toll-like receptor (TLR) activation, lymph nodes (LN) draining, and the suppression of antigen-specific immune responses in an ovalbumin protein model was investigated. Results Compared to unmodified ODN, lipid functionalized suppressive ODN demonstrated enhanced cellular uptake and TLR-9 specific immune suppression in TLR reporter cells. Additionally, injection of a low dose of lipid-modified suppressive ODN, but not the unconjugated ODN, accumulated in the draining LNs and exhibited potent inhibition of antigen-specific CD8+ T cell and B cell responses in vivo. Conclusions Targeting suppressive ODN to antigen presenting cells (APCs) in the local LNs is an effective approach to amplify the immune modulation mediated by ODN containing repetitive TTAGGG motif. This approach might be broadly applicable to target molecular adjuvants to the keyimmune cells in the LNs draining from disease site, providing a simple strategy to improve the efficacy of many molecular immune modulators.

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Structure, mechanism and therapeutic utility of immunosuppressive oligonucleotides

Cited by 29 publications

References 104 publications

Suppressive oligonucleotides inhibit inflammation in a murine model of mechanical ventilator induced lung injury

Suppressive oligonucleotides inhibit inflammation in a murine model of mechanical ventilator induced lung injury

The Potential of Telomeric G-Quadruplexes Containing Modified Oligoguanosine Overhangs in Activation of Bacterial Phagocytosis and Leukotriene Synthesis in Human Neutrophils

Targeting Suppressive Oligonucleotide to Lymph Nodes Inhibits Toll-like Receptor-9-Mediated Activation of Adaptive Immunity

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