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Circulating natural killer cells are phenotypically and functionally altered in age-related macular degeneration
Journal article   Open access   Peer reviewed

Circulating natural killer cells are phenotypically and functionally altered in age-related macular degeneration

Kiva Brennan, Ema Ozaki, Eleanor Noone, Sarah Palko, Kieran P Byrne, Fiona Roche, Matt McElheron, Kieva Byrne, Luke Gibbons, Katie Robb, …
Cell reports. Medicine, 102792
05/07/2026
DOI: 10.1016/j.xcrm.2026.102792
PMID: 42102824
url
https://doi.org/10.1016/j.xcrm.2026.102792View
Published (Version of record) Open Access

Abstract

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 (nAMD). 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 nAMD 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 nAMD and suggests harnessing NK cells represents an immunotherapeutic alternative for the treatment of nAMD.
 Immunotherapy natural killer cells neovascular choroidal neovascularization age-related macular degeneration IL-18

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