Macular degeneration involves the death of vital cells in the retina, leading to progressive blindness. The less common neovascular (or “wet”) form of the condition involves the inappropriate growth of leaky blood vessels in the retina and underlying choroid. Existing treatments focus on trying to prevent this blood vessel growth or remove the vessels, rather than addressing underlying causes. Here, researchers make a step in the direction of those underlying causes by identifying a problem immune cell population that appears to contribute to the dysfunction and leakage of blood vessels in the eye.
Age-related macular degeneration (AMD) is the leading cause of irreversible central blindness and can result in pathological neovascularization. Using a “human-first” approach, we identify immunotherapy as a disease modifier in models of neovascular AMD. Plasma cytokine analysis in a large population cohort reveals an imbalance of lymphocytic cytokines associated with severity of AMD, leading to discovery of a skewed peripheral natural killer (NK) cell phenotype in individuals with AMD.
Peripheral NK cells are rapidly activated in neovascular AMD models, and single-cell RNA sequencing demonstrates expansion of activated cytolytic NK cells within neovascular lesions during resolution. NK cells localize to neovessels in human AMD donor eyes; however, they exhibit markers of terminal differentiation and quiescence. Adoptive transfer of pre-activated NK cells reduces neovascularization and restores barrier integrity. Our data identify a distinct, functionally altered NK cell phenotype in neovascular AMD and suggests harnessing NK cells represents an immunotherapeutic alternative for the treatment of neovascular AMD.
