IL-18 Attenuates Experimental Choroidal Neovascularization as a Potential Therapy for Wet Age-Related Macular Degeneration

Doyle, Sarah; Ozaki, Ema; Brennan, Kiva; Humphries, Marian M.; Mulfaul, Kelly; Keaney, James; Kenna, Paul F.; Maminishkis, Arvydas; Kiang, Anna‐Sophia; Saunders, Sean P.; Hams, Emily; Lavelle, Ed C.; Gardiner, Clair M.; Fallon, Padraic G.; Adamson, Peter; Humphries, Peter; Campbell, Matthew

doi:10.1126/scitranslmed.3007616

Cited by 92 publications

(89 citation statements)

References 27 publications

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“…Recent research has indicated that IL-18 is correlated with the development of GA, 13 whereas IL-18 could inhibit the formation of CNV in a laser-induced model. 59 In our research, we found that A2E could inhibit COX2-PGE2 pathways to impede the suppressive function of RPE cells in Th1-cell differentiation. This finding indicated that COX2-PGE2 pathways mediated regulatory function of RPE cells in Th1 immunity in vitro.…”

Section: Discussionmentioning

confidence: 94%

“…*P < 0.05, **P < 0.01, ***P < 0.001, ns P > 0.05. mediators of CNV; in the LA-induced RPE damage, the expression of NO and PGE2, together with their precursors COX2 and iNOS, were found increasing in a CNV model. 58,59 The controversy about the proinflammatory and immune modulatory functions of COX2-PGE2 pathways in AMD might be related to the complex pathological feature of different AMD lesions (CNV or GA), just as the paradox roles of IL-18 in CNV and GA. Recent research has indicated that IL-18 is correlated with the development of GA, 13 whereas IL-18 could inhibit the formation of CNV in a laser-induced model.…”

Section: Discussionmentioning

confidence: 99%

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A2E Suppresses Regulatory Function of RPE Cells in Th1 Cell Differentiation Via Production of IL-1β and Inhibition of PGE2

Shi

Qiu

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Shi Q, Wang Q, Li J, et al. A2E suppresses regulatory function of RPE cells in Th1 cell differentiation via production of IL-1b and inhibition of PGE2. Invest Ophthalmol Vis Sci. 2015;56:7728-7738. DOI:10.1167/ iovs.15-17677 PURPOSE. Inflammatory status of RPE cells induced by A2E is essential in the development of AMD. Recent research indicated T-cell immunity was involved in the pathological progression of AMD. This study was designed to investigate how A2E suppresses immunoregulatory function of RPE cells in T-cell immunity in vitro. METHODS.Mouse RPE cells or human ARPE19 cells were stimulated with A2E, and co-cultured with naïve T cells under Th1, Th2, Th17, and regulatory T cell (Treg) polarization conditions. The intracellular cytokines or transcript factors of the induced T-cells subset were detected with flow cytometer and qRT-PCR. The ROS levels were detected, and the factors and possible pathways involved in the A2E-laden RPE cells were analyzed through neutralization antibody of IL-1b and inhibitors of related pathways. RESULTS.The A2E reduced regulatory function of RPE cells in Treg differentiation. The A2E-laden RPE cells promoted polarization of Th1 cells in vitro, but not Th2 or Th17 differentiation. The A2E induced RPE cells to release inflammatory cytokines and ROS, but PGE2 production was inhibited. Through neutralization of IL-1b or inhibition of COX2-PGE2 pathways, A2E-laden RPE cells expressed reduced effect in inducing Th1 cells. CONCLUSIONS.The A2E inhibited regulatory function of RPE cells in suppressing Th1 cell immunity in vitro through production of IL-1b and inhibition of PGE2. Our data indicate that A2E could suppress immunoregulatory function of RPE cells and adaptive immunity might play a role in the immune pathogenesis of AMD.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

A2E Suppresses Regulatory Function of RPE Cells in Th1 Cell Differentiation Via Production of IL-1β and Inhibition of PGE2

Shi

Qiu

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…However, a conglomeration of five laboratories determined that this finding was in fact due to glycerol, a proangiogenic excipient in the IL-18 neutralizing antibody preparation (27). Subsequently, it was reported that recombinant murine IL-18 reduced choroidal neovascularization in a laser injury model (28). However, a multicentered study failed to reproduce those data, finding instead that IL-18 had no effect on CNV over 5-log dose range, and instead that IL-18 induced RPE degeneration (27), which has been independently corroborated (29).…”

Section: Discussionmentioning

confidence: 99%

DICER1/ Alu RNA dysmetabolism induces Caspase-8–mediated cell death in age-related macular degeneration

Kim

Tarallo

Kerur

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Geographic atrophy, an advanced form of age-related macular degeneration (AMD) characterized by death of the retinal pigmented epithelium (RPE), causes untreatable blindness in millions worldwide. The RPE of human eyes with geographic atrophy accumulates toxic Alu RNA in response to a deficit in the enzyme DICER1, which in turn leads to activation of the NLRP3 inflammasome and elaboration of IL-18. Despite these recent insights, it is still unclear how RPE cells die during the course of the disease. In this study, we implicate the involvement of Caspase-8 as a critical mediator of RPE degeneration. Here we show that DICER1 deficiency, Alu RNA accumulation, and IL-18 up-regulation lead to RPE cell death via activation of Caspase-8 through a Fas ligand-dependent mechanism. Coupled with our observation of increased Caspase-8 expression in the RPE of human eyes with geographic atrophy, our findings provide a rationale for targeting this apoptotic pathway in this disease. macular degeneration | inflammasome | caspase

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“…5 The laser-induced CNV model was established as a highly reproducible model in nonhuman primates; however, its use in the mouse eye is less straightforward and appears susceptible to variability as highlighted by Poor et al 6 in a comprehensive study reported in 2014. Therefore, we assessed the efficacy response of mouse IL-18 (SB-528775; GlaxoSmithKline [GSK], Stevenage, UK) on the formation of neovascular lesions in the central region of the retinas of the recently described JR5558 mice, which develop bilateral spontaneous CNV and retinal angiomatous proliferation (RAP; Figs.…”

Section: Il-18 Prevents Spontaneous Neovascular Lesion Developmentmentioning

confidence: 99%

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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IL-18 Attenuates Experimental Choroidal Neovascularization as a Potential Therapy for Wet Age-Related Macular Degeneration

Cited by 92 publications

References 27 publications

A2E Suppresses Regulatory Function of RPE Cells in Th1 Cell Differentiation Via Production of IL-1β and Inhibition of PGE2

A2E Suppresses Regulatory Function of RPE Cells in Th1 Cell Differentiation Via Production of IL-1β and Inhibition of PGE2

DICER1/ Alu RNA dysmetabolism induces Caspase-8–mediated cell death in age-related macular degeneration

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

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