Suppressive Oligodeoxynucleotides Protect Mice from Lethal Endotoxic Shock

Shirota, Hidekazu; Gürsel, İhsan; Gürsel, Mayda; Klinman, Dennis M.

doi:10.4049/jimmunol.174.8.4579

Cited by 81 publications

(133 citation statements)

References 42 publications

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“…In accordance with these findings, we reported recently that the induction of CCL3 by non-CpG ODN derived from type B CpG ODN2006 is endosome acidification/ maturation dependent (5). However, a recent study indicated that suppressive ODNs inhibit LPS-mediated endotoxic shock by direct binding to STAT1 and STAT4 in macrophages (23) and that Bform DNA induces antiviral responses in a TLR-independent manner (45). In the current study, we found that rODNs that contain a G-rich PS backbone with no CpG motifs strongly activate IL-8 secretion while inhibiting HLA expression.…”

Section: Discussionsupporting

confidence: 71%

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Control of In Vitro Immune Responses by Regulatory Oligodeoxynucleotides through Inhibition of pIII Promoter Directed Expression of MHC Class II Transactivator in Human Primary Monocytes

Wang

Roderiquez

Jones

et al. 2007

The Journal of Immunology

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Ag presentation is a key step in the initiation of adaptive immune responses that depends on the expression of MHC Ags and costimulatory molecules. Immune-enhancing CpG and non-CPG oligodeoxynucleotides (ODNs) stimulate Ag presentation by stimulating the expression of these molecules and by promoting dendritic cell maturation. In this report, we identify immunoregulatory orthophosphorothioate non-CpG molecules, referred to as regulatory ODNs (rODNs), by their ability to inhibit allogeneic monocyte-stimulated T cell responses and down-regulate HLA-DR in human primary monocytes. The rODNs promoted the survival of macrophages and were able to activate IL-8 secretion through a chloroquine-resistant pathway. Messenger RNAs for HLA-DR α and β and the MHC CIITA were reduced by rODNs but not by stimulatory CpG ODN2006 and non-CpG ODN2006a. CIITA transcription in monocytes was controlled primarily by promoter III and not by promoter I or IV. rODNs blocked promoter III-directed transcription of CIITA in these cells. Under conditions that induced dendritic cell differentiation, rODNs also reduced HLA-DR expression. The activity of rODNs is phosphorothioate chemistry and G stretch dependent but TLR9 independent. G tetrads were detected by circular dichroism in active rODNs and associated with high m.w. multimers on nondenaturing gels. Heat treatment of rODNs disrupted G tetrads, the high m.w. aggregates, and the HLA-DR inhibitory activity of the ODNs. The inhibition of immune responses by regulatory oligodeoxynucleotides may be useful for the treatment of immune-mediated disorders including autoimmune diseases and graft rejection.

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Section: Discussionsupporting

confidence: 71%

“…Suppressive ODNs block the effects of stimulatory CpG ODNs in mouse B cells (20,21). Suppressive ODNs containing the TTAGGG motif suppress inflammatory cytokine production by interacting with STAT1 and STAT4 and also reduce CpG-induced arthritis (22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Control of In Vitro Immune Responses by Regulatory Oligodeoxynucleotides through Inhibition of pIII Promoter Directed Expression of MHC Class II Transactivator in Human Primary Monocytes

Wang

Roderiquez

Jones

et al. 2007

The Journal of Immunology

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“…Those studies established that a single dose of suppressive ODN reduced lung inflammation, weight loss, and improved the survival of mice challenged intratracheally with 0.25-2.5 mg of silica, but that two doses of suppressive ODN were more effective. Preliminary studies also established that the timing of suppressive ODN administration was relevant; optimal protection was observed when suppressive ODN were delivered shortly before exposure to the inflammatory stimulus (consistent with studies in which suppressive ODN mediated protection against toxic shock) (20).…”

Section: Figurementioning

confidence: 90%

“…Peritoneal cells were isolated from mice injected i.p. with 3% thioglycolate, as previously described (20). Single-cell suspensions were allowed to attach to the plate over 24 h and were then cultured with 20 -40 g/cm 2 of silica in 6-or 96-well plates.…”

Section: In Vitro Studiesmentioning

confidence: 99%

“…Suppressive ODN express motifs based on the repetitive TTAGGG hexamers present at high frequency in the telomeric ends of self DNA (15). Previous studies showed that these motifs (released by injured host cells) block Th1 and proinflammatory cytokine production in vitro and down-modulate over-exuberant/pathologic immune responses in vivo (such as those found in septic shock and autoimmune diseases) (15)(16)(17)(18)(19)(20).…”

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confidence: 99%

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Suppressive Oligodeoxynucleotides Inhibit Silica-Induced Pulmonary Inflammation

Sato¹,

Shimosato²,

Alvord

et al. 2008

The Journal of Immunology

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Inhalation of silica-containing dust particles induces silicosis, an inflammatory disease of the lungs characterized by the infiltration of macrophages and neutrophils into the lungs and the production of proinflammatory cytokines, chemokines, and reactive oxygen species (ROS). Synthetic oligodeoxynucleotides (ODN) expressing “immunosuppressive motifs” were recently shown to block pathologic inflammatory reactions in murine models of autoimmune disease. Based on those findings, the potential of suppressive ODN to prevent acute murine silicosis was examined. In vitro studies indicate that suppressive ODN blunt silica-induced macrophage toxicity. This effect was associated with a reduction in ROS production and p47phox expression (a subunit of NADPH oxidase key to ROS generation). In vivo studies show that pretreatment with suppressive (but not control) ODN reduces silica-dependent pulmonary inflammation, as manifest by fewer infiltrating cells, less cytokine/chemokine production, and lower levels of ROS (p < 0.01 for all parameters). Treatment with suppressive ODN also reduced disease severity and improved the survival (p < 0.05) of mice exposed to silica.

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DNA‐Based Biomaterials for Immunoengineering

Maeda

Kojima

Song

et al. 2018

Adv Healthcare Materials

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of extracellular DNA in tissues and in circulation. [5] Extracellular DNA is capable of engaging with the immune system as depicted in Figure 1; therefore, as synthetic DNA-based biomaterials emerge, their potential immune responses must be considered. DNA sensors are mediators of extracellular DNA immune responses observed in vivo, including cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and toll-like receptors (TLRs). Defining novel DNA sensors and their mechanisms is an active area of investigation. [6] Likewise, the structural and chemical properties of DNA that triggers DNA sensors continue to be uncovered. [6] This review summarizes known DNA interaction modalities with the immune system, the sources of extracellular DNA, and, finally, the relevant and emerging biotechnologies that incorporate DNA molecules. A focus is geared toward innate immune responses and doublestranded DNA (dsDNA). Leveraging the immunomodulatory capacity of DNA enables tailoring materials to initiate specific immune outcomes depending on the application, for instance, priming aggressive immune responses for localized tumor-interfacing biomaterials or immunosuppressive functions to prevent chronic inflammation on implant surfaces. Achieving this requires an improved understanding of the DNA properties, such as backbone chemistry, base pair sequence, charge, and length, that can function as design levers for the immune response. The Role of Extracellular DNA in the Immune ResponseThe immune system is designed to protect the host against infections by distinguishing between self-and non-self motifs, and by identifying pathogen and damage signals. Upon recognition of a "non-self" or foreign molecule, an array of effector functions are triggered and orchestrated by immune cells to achieve pathogen clearance and restore homeostasis. [7] These immunoactivating defense mechanisms include the release of proinflammatory cytokines, immune cell recruitment, programmed cell death, and phagocytosis. Ideally, immunoactivating responses are supplanted by immunosuppressive functions once the pathogen or agonist is resolved. This immune resolution is necessary to coordinate healing and anti-inflammatory functions such as diminished chemokine and cytokine secretion, replacement Man-made DNA materials hold the potential to modulate specific immune pathways toward immunoactivating or immunosuppressive cascades. DNAbased biomaterials introduce DNA into the extracellular environment during implantation or delivery, and subsequently intracellularly upon phagocytosis or degradation of the material. Therefore, the immunogenic functionality of biological and synthetic extracellular DNA should be considered to achieve desired immune responses. In vivo, extracellular DNA from both endogenous and exogenous sources holds immunoactivating functions which can be traced back to the molecular features of DNA, such as sequence and length. Extracellular DNA is recognized as damage-associated molecular patterns (DAMPs), or pathogen-associated mole...

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Suppressive Oligodeoxynucleotides Protect Mice from Lethal Endotoxic Shock

Cited by 81 publications

References 42 publications

Control of In Vitro Immune Responses by Regulatory Oligodeoxynucleotides through Inhibition of pIII Promoter Directed Expression of MHC Class II Transactivator in Human Primary Monocytes

Control of In Vitro Immune Responses by Regulatory Oligodeoxynucleotides through Inhibition of pIII Promoter Directed Expression of MHC Class II Transactivator in Human Primary Monocytes

Suppressive Oligodeoxynucleotides Inhibit Silica-Induced Pulmonary Inflammation

DNA‐Based Biomaterials for Immunoengineering

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