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. 2026 Jan 2.
doi: 10.1097/TP.0000000000005608. Online ahead of print.

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

James A Keiler  1 , Jakob G Habib  1 , Ji W Han  1 , Bobbi J Wilson  1 , Lizheng Guo  1 , Joe B Jenkins  2 , A Brad Farris  1 , Ian N Moore  2 , William H Kitchens  1 , Kristin M Whitworth  3 , Andrew B Adams  4 , R Paul Johnson  2 , Christian P Larsen  1 , Mandy L Ford  1 , Steven C Kim  1
Affiliations

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

James A Keiler et al. Transplantation. .

Abstract

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.

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Conflict of interest statement

The authors declare no conflicts of interest.

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