A suppressive oligodeoxynucleotide inhibits ocular inflammation

Fujimoto, Chiaki; Klinman, Dennis M.; Shi, Guangpu; Yin, Hongen; Vistica, Barbara P.; Lovaas, Jenna D.; Wawrousek, Eric F.; Igarashi, Tsutomu; Chan, Chi‐Chao; Gery, Igal

doi:10.1111/j.1365-2249.2009.03918.x

Cited by 19 publications

(25 citation statements)

References 38 publications

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“…Our study has demonstrated that suppressive ODN can block immune responses mediated by endotoxin in the eye (an immune privileged site), an established animal model of acute ocular inflammation. Recently, Fujimoto et al (40) reported that suppressive A151 ODN can inhibit ocular inflammation in two murine models, IRBP (interphotoreceptor retinoid-binding protein)-induced experimental autoimmune uveitis and adoptively transferred ocular inflammation. These forms are antigen-driven and, compared with LPS, are significantly less aggressive forms of experimental uveitis models.…”

Section: Discussionmentioning

confidence: 99%

Mammalian Telomeric DNA Suppresses Endotoxin-induced Uveitis

Yagci

Aslan

Gürsel

et al. 2010

Journal of Biological Chemistry

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Telomeric regions of mammalian chromosomes contain suppressive TTAGGG motifs that inhibit several proinflammatory and Th1-biased immune responses. Synthetic oligodeoxynucleotides (ODN) expressing suppressive motifs can reproduce the down-regulatory activity of mammalian telomeric repeats and have proven effective in the prevention and treatment of several autoimmune and autoinflammatory diseases. Endotoxin-induced uveitis (EIU) is an established animal model of acute ocular inflammation induced by LPS administration. Augmented expression of proinflammatory cytokines/chemokines such as TNF␣, IL-6, and MCP1 and bactericidal nitric oxide production mediated by LPS contribute to the development of EIU. Suppressing these mediators using agents that are devoid of undesirable systemic side effects may help prevent the development of EIU. This study demonstrates the selective down-regulatory role of suppressive ODN after (i) local or (ii) systemic treatment in EIU-induced rabbits and mice. Our results indicate that suppressive ODN down-regulate at both the transcript and protein levels of several proinflammatory cytokines and chemokines as well as nitric oxide and co-stimulatory surface marker molecules when administrated prior to, simultaneously with, or even after LPS challenge, thereby significantly reducing ocular inflammation in both rabbit and mouse eyes. These findings strongly suggest that suppressive ODN is a potent candidate for the prevention of uveitis and could be applied as a novel DNAbased immunoregulatory agent to control other autoimmune or autoinflammatory diseases.DNA and RNA are the essential components of all living organisms. Accumulated evidence strongly suggests that these nucleic acids have multiple and complex effects on the immune system and are more than a blueprint of life (1, 2). On one hand, due to their high unmethylated CpG motif frequency, bacterial DNAs are recognized as "non-self" via TLR9 (Toll-like receptor 9) and trigger an innate immune response characterized by the proliferation and maturation of B cells, natural killer cells, and plasmacytoid dendritic cells and the secretion of T-helper 1-type cytokines, chemokines, and/or multivalent immunoglobulins (3-8). On the other hand, telomeric regions of mammalian chromosomes contain suppressive TTAGGG motifs that can inhibit several TLR-dependent and TLR-independent Th1-mediated immune responses. Of note, these motifs are underrepresented in the prokaryotic genome. Synthetic singlestranded oligodeoxynucleotides (ODN) 3 containing repetitive TTAGGG motifs mimic this effect (1, 9 -11). Previous studies revealed that deleterious inflammatory responses to a host can be down-regulated by suppressive ODN. In vitro, suppressive ODN inhibits the production of several proinflammatory cytokines and chemokines induced by bacteria (1,(12)(13)(14). Furthermore, in vivo suppressive ODN administration reduces the frequency and severity of several autoimmune and inflammatory diseases such as arthritis, systemic lupus erythematosus, pulmonary inflam...

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Section: Discussionmentioning

confidence: 99%

Mammalian Telomeric DNA Suppresses Endotoxin-induced Uveitis

Yagci

Aslan

Gürsel

et al. 2010

Journal of Biological Chemistry

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“…Other approaches such as Amino acid copolymers [173], siRNA against inducible co-stimulator (ICOS) [174], IL-1 receptor agonist [175], Dexamethasone [176], angiotensin II type 1 receptor blocker Telmisartan [177, 178], glucosamine [179], vaclosporin (LX211) [180], chitinase inhibitors [181], vascular adhesion protein-1 inhibitors [182], methylprednisolone acetate [183], cloricromene, a coumarin derivative [184], vasoactive intestinal peptide-loaded liposomes [185], oligodeoxynucleotide [186], DAF [187] and gene therapy [190] have been shown to contain inflammation in the experimental model of uveitis. Most of these experimental studies present an opportunity to explore novel therapeutic methods for uveitis, which includes sight-threatening diseases such as Behcet disease, birdshot retinochoroidopathy, Vogt- Koyanagi-Harada, sympathetic ophthalmia and ocular sarcoidosis.…”

Section: Antioxidant Treatments For Uveitismentioning

confidence: 99%

Emerging Role of Antioxidants in the Protection of Uveitis Complications

Yadav

Kalariya

Ramana³

2011

CMC

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Current understanding of the role of oxidative stress in ocular inflammatory diseases indicates that antioxidant therapy may be important to optimize the treatment. Recently investigated antioxidant therapies for ocular inflammatory diseases include various vitamins, plant products and reactive oxygen species scavengers. Oxidative stress plays a causative role in both non-infectious and infectious uveitis complications, and novel strategies to diminish tissue damage and dysfunction with antioxidant therapy may ameliorate visual complications. Preclinical studies with experimental animals and cell culture demonstrate significance of anti-inflammatory effects of a number of promising antioxidant agents. Many of these antioxidants are under clinical trial for various inflammatory diseases other than uveitis such as cardiovascular, rheumatoid arthritis and cancer. Well planned interventional clinical studies of the ocular inflammation will be necessary to sufficiently investigate the potential medical benefits of antioxidant therapies for uveitis. This review summarizes the recent investigation of novel antioxidant agents for ocular inflammation, with selected studies focused on uveitis.

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“…While phosphorothioate ODN can exert sequence non-specific immune effects at the high concentrations used by Kim et al [38;39], the control ODN used in our studies and by other groups uniformly failed to increase T reg development and/or function [37;40–42]. Similarly, studies performed by multiple groups show that suppressive but not control ODN down regulate inflammatory and autoimmune responses in vivo [5;6;31–33]. …”

Section: Discussionmentioning

confidence: 49%

“…Sup ODN contain multiple TTAGGG motifs identical to those found at high frequency in mammalian telomeres and mimic the ability of telomeric DNA to reduce inflammation and autoimmune reactions [5;6;31–33]. Previous studies found that Sup ODN inhibited the differentiation of naive CD4 + cells into Th1 effectors [7;8].…”

Section: Discussionmentioning

confidence: 99%

Suppressive oligodeoxynucleotides promote the generation of regulatory T cells by inhibiting STAT1 phosphorylation

Bode

Wang

Klinman

2014

International Immunopharmacology

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Suppressive oligodeoxynucleotides (Sup ODN) express repetitive TTAGGG motifs that have proven useful in the treatment/prevention of numerous inflammatory and autoimmune diseases. The mechanism underlying the immunosuppressive activity of Sup ODN is incompletely understood. Regulatory T cells (Treg) play a key role in are generated from controlling a variety of pathologic autoimmune responses. Tregs activated CD4+ T cells in a process that involves the phosphorylation of STAT family members. Current studies demonstrate that Sup ODN promote the differentiation of CD4+CD25− T cells into functionally active iTreg in vitro. When administered in vivo, Sup in response to peptide challenge. Central to this ODN promote the generation of iTreg effect is the ability of Sup ODN to block the phosphorylation of STAT1. These findings clarify the mechanism underlying the therapeutic activity of Sup ODN and support their use in Treg-based immunotherapy.

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A suppressive oligodeoxynucleotide inhibits ocular inflammation

Cited by 19 publications

References 38 publications

Mammalian Telomeric DNA Suppresses Endotoxin-induced Uveitis

Mammalian Telomeric DNA Suppresses Endotoxin-induced Uveitis

Emerging Role of Antioxidants in the Protection of Uveitis Complications

Suppressive oligodeoxynucleotides promote the generation of regulatory T cells by inhibiting STAT1 phosphorylation

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