IL18 is not therapeutic for neovascular age-related macular degeneration

Abstract

Purpose: Recent studies report apparently conflicting roles for the inflammasome effector IL18 in the development of age-related macular degeneration. Whereas IL18 has been demonstrated to induce RPE degeneration in atrophic AMD, it has also been promoted as a potential therapeutic to prevent neovascular AMD. The purpose of this multi-centered study was to evaluate whether IL18 possesses anti-angiogenic potential in preventing laser induced choroidal neovascularization, and to evaluate the toxicity of IL18 administration.

Methods: Five independent laboratories administered a 4-log dose range (1 to 1,000 ng) of recombinant mouse IL18 into the vitreous humor of wild-type mice undergoing laser injury. Several anti-IL18 antibodies were tested for their ability to influence CNV volume in wild-type and IL18-deficient mice. Seven and 14 days later, CNV volumes were assessed. ERGs, RPE flat mount and histology were utilized to examine retinal health after IL18 injection. Finally, mice genetically or pharmacologically deficient in Nlrp3, Pycard, or Caspase-1, which form the inflammasome complex that bioactivates IL18, were analyzed for their angiogenic response.

Results: Of the five participating laboratories, none found that administration of recombinant IL18 changed CNV volume. Further, administration of recombinant IL18 caused RPE degeneration and ERG a-wave and b-wave depression. Mice deficient in essential components of the Nlrp3 inflammasome exhibited no significant changes in CNV volume compared to control animals. The major IL18 receptor, IL18R1 is abundantly expressed in normal healthy human retina, which further supports the concept that IL18 treatment is ill-advised in human patients. Surprisingly, in agreement with a previous report, we found that one particular IL18 neutralizing antibody increased CNV volume not only in wild-type but also in IL18-deficient mice. However, we determined that this effect was due to a pro-angiogenic effect of glycerol in the antibody preparation mediated via aquaporin-1, rather than from target-specific IL18 blockade.

Conclusions: This study confirms that IL18 induces RPE degeneration, argues against pursuing IL18 as a therapeutic agent for neovascular age-related macular degeneration, and cautions that antibody preparations containing glycerol must be carefully monitored for potential confounding pro-angiogenic effects.

Keywords: 695 retinal degenerations: cell biology • 453 choroid: neovascularization • 490 cytokines/chemokines