Interleukin‐18 Has Antipermeablity and Antiangiogenic Activities in the Eye: Reciprocal Suppression With VEGF

Shen, Jikui; Choy, David F.; Yoshida, Tomoo; Iwase, Takeshi; Hafiz, Gulnar; Xie, Bing; Hackett, Sean F.; Arron, Joseph R.; Campochiaro, Peter A.

doi:10.1002/jcp.24575

Cited by 47 publications

(42 citation statements)

References 48 publications

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“…Our data pertaining to a role for IL-18 in regulating neovascularization was supported by independent reports in the literature, 10,11 and strongly indicated that IL-18 could have some therapeutic benefit in neovascular AMD, in contrast to a report by Ambati et al 12 Human IL-18 (SB-485232, GSK) is a clinically enabled investigational drug that has been injected systemically in >170 cancer patients with an excellent safety profile, with numerous on-going studies. 13,14 We sought to examine the tolerability and efficacy of SB-485232 in a nonhuman primate model of neovascular AMD.…”

Section: Mature Il-18 Is Safe and Reduces Development Of Laser-inducecontrasting

confidence: 53%

IL-18 Immunotherapy for Neovascular AMD: Tolerability and Efficacy in Nonhuman Primates

Doyle

López

Celkova

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Age-related macular degeneration is the most common form of central retinal blindness in the elderly. Of the two end stages of disease, neovascular AMD-although the minority formis the most severe. Current therapies are highly successful at controlling progression of neovascular lesions; however, a significant number of patients remain refractory to treatment and the development of alternative and additive therapies to anti-VEGFs is essential.METHODS. In order to address the translational potential of interleukin (IL)-18 for use in neovascular AMD, we initiated a nonhuman primate tolerability and efficacy study for the use of intravitreally (IVT) administered clinical grade human IL-18 (SB-485232). Cynomolgus monkeys were injected IVT with increasing doses of human IL-18 (two each at 1000, 3000, and 10,000 ng per eye). In tandem, 21 monkeys were administered nine laser burns in each eye prior to receiving IL-18 as an IVT injection at a range of doses. Fundus fluorescein angiography (FFA) was performed on days 8, 15, and 22 post injection and the development of neovascular lesions was assessed.RESULTS. We show intravitreal, mature, recombinant human IL-18 is safe and can reduce choroidal neovascular lesion development in cynomolgus monkeys.CONCLUSIONS. Based on our data comparing human IL-18 to current anti-VEGF-based therapy, clinical deployment of IL-18 for neovascular AMD has the potential to lead to a new adjuvant immunotherapy-based treatment for this severe form of central blindness.

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Section: Mature Il-18 Is Safe and Reduces Development Of Laser-inducecontrasting

confidence: 53%

IL-18 Immunotherapy for Neovascular AMD: Tolerability and Efficacy in Nonhuman Primates

Doyle

López

Celkova

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…The exact role of IL-18 in the eye is still unclear, 51 but VEGF and IL-18 were shown to suppress each other's production. 52 In a mouse model of neovascularization, 53 IL-18 inhibited new vessel formation but promoted damage to the RPE that mimics aspects of the dry form of AMD. 54 Alteration of RPE cells after mast cell degranulation could thus be at least in part related to IL-18 increase.…”

Section: And In Retinalmentioning

confidence: 98%

Choroidal Mast Cells in Retinal Pathology

Bousquet

Zhao

Thillaye-Goldenberg

et al. 2015

The American Journal of Pathology

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Mast cells are important in the initiation of ocular inflammation, but the consequences of mast cell degranulation on ocular pathology remain uncharacterized. We induced mast cell degranulation by local subconjunctival injection of compound 48/80. Initial degranulation of mast cells was observed in the choroid 15 minutes after the injection and increased up to 3 hours after injection. Clinical signs of anterior segment inflammation paralleled mast cell degranulation. With the use of optical coherence tomography, dilation of choroidal vessels and serous retinal detachments (SRDs) were observed and confirmed by histology. Subconjunctival injection of disodium cromoglycate significantly reduced the rate of SRDs, demonstrating the involvement of mast cell degranulation in posterior segment disorders. The infiltration of polymorphonuclear and macrophage cells was associated with increased ocular media concentrations of tumor necrosis factor-α, CXCL1, IL-6, IL-5, chemokine ligand 2, and IL-1β. Analysis of the amounts of vascular endothelial growth factor and IL-18 showed an opposite evolution of vascular endothelial growth factor compared with IL-18 concentrations, suggesting that they regulate each other's production. These findings suggest that the local degranulation of ocular mast cells provoked acute ocular inflammation, dilation, increased vascular permeability of choroidal vessels, and SRDs. The involvement of mast cells in retinal diseases should be further investigated. The pharmacologic inhibition of mast cell degranulation may be a potential target for intervention.

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“…41 So far, a series of previous studies have investigated the role of IL-18 in the physiological and pathological angiogenesis. For instance, in mice with ischemic retinopathy, intraocular injection of IL-18 suppresses leakage and neovascularization caused by vascular endothelial growth factor, 42 suggesting that IL-18 inhibits vascular endothelial growth factor-dependent induction of proangiogenic status. On the other hand, IL-18 promotes migration and tube formation by human microvascular endothelial cells in vitro, indicating its pro-angiogenic property.…”

Section: Discussionmentioning

confidence: 99%

Serum levels of interleukin‐18‐binding protein isoform a: Clinical association with inflammation and pulmonary hypertension in systemic sclerosis

Nakamura

Asano

Taniguchi

et al. 2016

The Journal of Dermatology

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Systemic sclerosis (SSc) is a chronic autoimmune inflammatory disease characterized by extensive tissue fibrosis and various vascular complications. A wealth of evidence suggests the substantial contribution of pro-inflammatory cytokines to the development of SSc, but the role of interleukin (IL)-18 signaling in this disease still remains elusive. To address this issue, we herein determined serum levels of IL-18-binding protein isoform a (IL-18BPa), a soluble decoy receptor for IL-18, by enzyme-linked immunosorbent assay in 57 SSc patients and 20 healthy controls and evaluated their clinical correlation. Serum IL-18BPa levels were higher in SSc patients than in healthy controls, while comparable between diffuse cutaneous SSc and limited cutaneous SSc patients. Although serum IL-18BPa levels were not associated with dermal and pulmonary fibrotic parameters in SSc patients, there was a significant positive correlation between serum IL-18BPa levels and right ventricular systolic pressure estimated by echocardiography. Furthermore, in 24 SSc patients who underwent right heart catheterization, serum IL-18BPa levels positively correlated with mean pulmonary arterial pressure. As for systemic inflammatory markers, significant positive correlations of circulating IL-18BPa levels with erythrocyte sedimentation rate and C-reactive protein were noted. These results suggest that the inhibition of IL-18 signaling by IL-18BPa may be involved in the development of pulmonary vascular involvement leading to pulmonary hypertension and modulate the systemic inflammation in SSc.

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Interleukin‐18 Has Antipermeablity and Antiangiogenic Activities in the Eye: Reciprocal Suppression With VEGF

Cited by 47 publications

References 48 publications

IL-18 Immunotherapy for Neovascular AMD: Tolerability and Efficacy in Nonhuman Primates

IL-18 Immunotherapy for Neovascular AMD: Tolerability and Efficacy in Nonhuman Primates

Choroidal Mast Cells in Retinal Pathology

Serum levels of interleukin‐18‐binding protein isoform a: Clinical association with inflammation and pulmonary hypertension in systemic sclerosis

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