Adjuvant IL-15 Blockade Significantly Improves Survival in a CD28-based Immunosuppression Protocol of Pig-to-nonhuman Primate Renal Xenotransplantation

BACKGROUND: Xenotransplantation has emerged as a promising solution to the critical organ shortage, with encouraging results in preclinical nonhuman primate studies and recent first-in-human transplants. Our group previously performed pig-to-rhesus macaque renal xenotransplants using the clinically available costimulation blockade agent belatacept; however, graft survival was modest (>1 moh). Analysis of rejected xenografts identified natural killer (NK) cells as a predominant infiltrating population. METHODS: In this study, we investigated whether adding adjuvant αIL-15-an agent known to suppress T-cell subsets and deplete NK cells in rhesus macaques-could improve xenograft survival. αIL-15 was combined with a clinically relevant immunosuppressive regimen comprising T-cell depletion, belatacept, mycophenolate mofetil, and steroids. RESULTS: We found that the addition of αIL-15 significantly improved xenograft survival and function. Longitudinal analysis of NK cell subsets revealed a shift from a predominant cytotoxic CD16 + CD56 - population to a double-negative CD16 - CD56 - phenotype following αIL-15 treatment. CONCLUSIONS: These findings deepen our understanding of NK cell subsets and their potential contributions to xenograft injury and suggest that targeted modulation of NK cell populations can enhance xenograft outcomes in a preclinical pig-to-rhesus macaque model of renal xenotransplantation.