Effects of Systemic and Intravitreal TNF-α Inhibition in Experimental Autoimmune Uveoretinitis

Busch, Martin; Bauer, Dirk; Hennig, Maren; Wasmuth, Susanne; Thanos, Solon; Heiligenhaus, Arnd

doi:10.1167/iovs.12-10138

Cited by 23 publications

(19 citation statements)

References 54 publications

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“…For adoptive transfer, splenocytes from immunized mice were collected 21 days after immunization and stimulated in vitro with 20 μg/mL hIRBP p161-180 for 72 h. Then, 2.5 × 10 7 cultured cells were injected intraperitoneally into naïve B10.RIII mice [26] .…”

Section: Eau Inductionmentioning

confidence: 99%

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

Bauer

Busch²,

Pacheco-López³

et al. 2017

Neuroimmunomodulation

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Objective: We examined the role of behavioral conditioning of immune responses with cyclosporine A (CsA) on the development of Th1/Th17-driven experimental autoimmune uveoretinitis (EAU). Methods: Mice received a 0.2% w/v saccharin solution as conditioned stimulus combined with CsA (20 mg/kg) in 6 association trials at 72-h intervals. For evocation periods, conditioned mice were reexposed to saccharin, whereas the conditioned but not reexposed group received water only. Animals were immunized with human interphotoreceptor-retinoid-binding protein peptide 161-180 (hIRBP_p161-180) peptide in complete Freund adjuvant (CFA) and a concomitant injection of pertussis toxin. Results: In naïve mice subjected to the behavioral conditioning regimen, mitogen-induced interleukin (IL)-2 production was decreased in conditioned mice compared to conditioned but not reexposed animals. Incidence and severity of EAU were not significantly lower in behaviorally conditioned and immunized mice. ELISA analysis of splenocytes revealed a reduced interferon (IFN)-γ/IL-17 ratio in CsA-treated, conditioned but not reexposed, and conditioned animals. The adoptive transfer of antigen-specific splenocytes from animals behaviorally conditioned with CsA to naïve mice decreased the severity of EAU in recipient mice compared to the control group. In vitro activation of splenocytes isolated from immunized mice with agonists targeting TLR2 and NOD2 together with β₂-adrenergic activation (induced by epinephrine, norepinephrine, or salbutamol) resulted in decreased IFN-γ but increased IL-17 immune responses. The β₂-adrenergic antagonist propranolol could restore IFN-γ production, whereas only the norepinephrine-induced increase in IL-17 production was abrogated. Conclusions: We conclude that CsA conditioning in the EAU model mitigates Th1 but enhances Th17 immune responses, and does not ameliorate disease. The results imply that in EAU the mechanism of immune conditioning interacts with CFA components during active immunization, most likely via the TLR2/NOD2 pathway, and induces differentiation of Th17 cells that drive autoimmune diseases.

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Section: Eau Inductionmentioning

confidence: 99%

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

Bauer

Busch²,

Pacheco-López³

et al. 2017

Neuroimmunomodulation

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“…They found that after systemic treatment with etanercept in the afferent phase, EAU disease scores, IRBP-specific cell proliferation, and production of Th1, Th2, and Th17 cytokines were reduced. EAU also improved after intravitreal etanercept treatment in the afferent phase [11].…”

Section: Discussionmentioning

confidence: 83%

“…This agent inhibits the action of both TNF-α and TNF-β, important pro-inflammatory cytokines [5][6][7][8][9][10][11]. Etanercept is a large molecule with a molecular weight of 150 kDa.…”

Section: Discussionmentioning

confidence: 99%

“…Etanercept is a large molecule with a molecular weight of 150 kDa. It binds to TNF-α and decreases its effect in disorders involving excess inflammation in humans and animals, including autoimmune diseases such as ankylosing spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and potentially, in various disorders mediated by excess TNF-α such as uveitis [5][6][7][8][9][10][11]36].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have been shown that systemically etanercept is efficious in the treatment in both the patients with chronic uveitis and experimental autoimmune uveitis (EAU) [8][9][10]. In a recent experimental study, it was also demonstrated that intravitreal etanercept was effective for the treatment of EAU [11]. Because of the adverse effects of systemic TNF-α inhibition, intravitreal administration of the drug may be more adequate to avoid these side effects.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The comparison of the effects of etanercept, cyclosporine A and triamcinolon acetonide on Th17 in experimental autoimmune uveitis

Demır¹,

Keleş²,

Çobanoğlu³

et al. 2016

New Front Ophthalmol

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Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation

Ratay

Bellotti

Gottardi³

et al. 2017

Adv Healthcare Materials

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Dry eye disease (DED), age-related macular degeneration (AMD), and Uveitis are ocular diseases that significantly affect the quality of life of millions of people each year. In these diseases, the action of chemokines, pro-inflammatory cytokines, and immune cells drives a local inflammatory response that results in ocular tissue damage. Multiple therapeutic strategies have been developed to either address the symptoms or abate the underlying cause of these diseases. Herein, we will review the challenges to deliver drugs to the relevant location in the eye for each of these diseases as well as current and innovative therapeutic approaches that attempt to restore homeostasis within the ocular microenvironment.

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Effects of Systemic and Intravitreal TNF-α Inhibition in Experimental Autoimmune Uveoretinitis

Abstract: It can be concluded that TNF-α participates mainly in the immunopathology in the induction phase of EAU. The mechanism of action underlying EAU improvement may be different for local and systemic etanercept treatment.

Cited by 23 publications

References 54 publications

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis

The comparison of the effects of etanercept, cyclosporine A and triamcinolon acetonide on Th17 in experimental autoimmune uveitis

Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation

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