Etanercept treatment in the endotoxin-induced uveitis of rats

Avunduk, Mustafa Cihat; Avunduk, Avni Murat; Öztekin, Esma; Baltacı, Abdülkerim Kasım; Özyazgan, Yılmaz; Mogolkoc, Rasim

doi:10.1016/j.exer.2004.06.001

Cited by 41 publications

(25 citation statements)

References 21 publications

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“…Decreasing only the ocular TNF-a levels reduced the rolling and the number of cells infiltrating ocular tissues, and the protein exudation in aqueous humor, correlating well with the ocular effects observed after systemic TNF-a blockade using etanercept or infliximab in EIU models. 2,21,32 We could also demonstrate that after local treatment, the activation state of infiltrating and resident monocytes was impaired as demonstrated by a reduction of iNOS expression and a change in the shape and distribution of those cells. The downregulation of IL-6 pro-inflammatory mediator, associated with an upregulation of the IL-10 anti-inflammatory molecule, favors the hypothesis of a subsequent modulation of the cytokines ocular profile by the local blockade of TNF-a.…”

Section: Discussionmentioning

confidence: 65%

“…1,[7][8][9][10]21,23,24 In rat eye with EIU, the p75 TNF-a soluble receptor-IgG1 fusion protein (etanercept) significantly reduced the uveitis scores and cell infiltration in ocular tissues when administered 24 h before disease . 23 In a rabbit model of EIU, infliximab at a dose of 20 mg kg À1 was given intravenously 24 h before the lipopolysaccharide (LPS) challenge, resulting in a significant reduction in the clinical scores of uveitis, together with a reduced number of cell infiltration and protein exudation. 21 In experimental EAU in rats, neutralization of TNF-a using a p55 TNF-a receptor conjugated with IgG (p55-Rc-IgG fusion protein), injected systemically, resulted in a delayed onset of clinical signs of uveitis without decreasing significantly the severity of the disease.…”

Section: Discussionmentioning

confidence: 99%

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Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

et al. 2009

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Intraocular inflammation has been recognized as a major factor leading to blindness. Because tumor necrosis factor-a (TNF-a) enhances intraocular cytotoxic events, systemic anti-TNF therapies have been introduced in the treatment of severe intraocular inflammation, but frequent re-injections are needed and are associated with severe side effects. We have devised a local intraocular nonviral gene therapy to deliver effective and sustained anti-TNF therapy in inflamed eyes. In this study, we show that transfection of the ciliary muscle by plasmids encoding for three different variants of the p55 TNF-a soluble receptor, using electrotransfer, resulted in sustained intraocular secretion of the encoded proteins, without any detection in the serum. In the eye, even the shorter monomeric variant resulted in efficient neutralization of TNF-a in a rat experimental model of endotoxininduced uveitis, as long as 3 months after transfection. A subsequent downregulation of interleukin (IL)-6 and iNOS and upregulation of IL-10 expression was observed together with a decreased rolling of inflammatory cells in anterior segment vessels and reduced infiltration within the ocular tissues. Our results indicate that using a nonviral gene therapy strategy, the local self-production of monomeric TNF-a soluble receptors induces a local immunomodulation enabling the control of intraocular inflammation.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

et al. 2009

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“…Avunduk et al [42] successfully used etanercept in the endotoxin-induced model (EIU) and Koizumi et al [43] showed that etanercept significantly reduces leukocyte rolling and adhesion in the EIU model; however, etanercept cannot be routinely used because of its tendency to induce the uveitic process in humans [18]. …”

Section: Adalimumab In Ophthalmologymentioning

confidence: 98%

Adalimumab (Humira™): a promising monoclonal anti-tumor necrosis factor alpha in ophthalmology

Neri

Zucchi

Allegri³

et al. 2011

Int Ophthalmol

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Tumor necrosis factor alpha (TNF-α) is a key soluble mediator involved in the inflammatory cascade of many disorders including uveitis. Among the anti-TNF-α agents, one of the most used in immune-mediated diseases, such as inflammatory arthropathies, is adalimumab (Humira™, Abbott Pharmaceutical Inc.), a fully humanized antibody. The purpose of this review is to analyze the main pharmacological and clinical aspects of adalimumab and its efficacy both in systemic and ocular inflammatory disorders. Adalimumab was effective in treating several autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. In recent years, adalimumab has been used successfully in refractory cases of intraocular inflammation. Moreover, this biological agent showed good safety and efficacy profiles in ocular use including childhood uveitis. Switching from other anti-TNF-α agents to adalimumab may offer several advantages, such as easier administration, better patient compliance, and lower rate of adverse events. Adalimumab is a promising drug for the therapy of uveitis, although further studies are needed on its application in uveitis.

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“…However, long-term treatment with these drugs may have grave side effects such as increased intraocular pressure (36) and cytotoxicity (37) and thus limit their use (25,33,35). Therefore, a new therapeutic strategy is urgently needed (38,39). The mechanism of action of this novel ODN-based immunosuppressive drug candidate is currently unknown.…”

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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Etanercept treatment in the endotoxin-induced uveitis of rats

Cited by 41 publications

References 21 publications

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

Adalimumab (Humira™): a promising monoclonal anti-tumor necrosis factor alpha in ophthalmology

Mammalian Telomeric DNA Suppresses Endotoxin-induced Uveitis

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