CD94-targeted depletion reduces natural killer cells and attenuates mouse kidney ischemia-reperfusion injury and subsequent acute lung injury

Kidney transplant benefit is limited by delayed graft function, a syndrome stemming from severe ischemia-reperfusion injury (IRI). Natural killer (NK) cells have been implicated in rejection and injury pathologies, motivating translatable strategies to target these cells. We investigated whether monoclonal antibody depletion of CD94-expressing immune cells attenuates injury in 2 clinically relevant mouse models of kidney IRI. High-dimensional flow cytometry demonstrated rapid expansion of NK cell populations following injury. Anti-CD94 therapy reduced NK cell frequency and activation after IRI in the kidney, and improved renal function and reduced histologic injury. Notably, kidney IRI induced acute lung injury with NK and T cell inflammation, hypoxemia, and histologic damage. Anti-CD94 therapy preceding kidney IRI abrogated all metrics of acute lung injury by 48 hours relative to isotype control. Finally, in orthotopic allogeneic kidney transplant models, anti-CD94 treatment was associated with reduced injury and improved observed survival relative to isotype control. These findings implicate CD94⁺ NK cells in early transplant-associated injury and support further evaluation of anti-CD94 treatment to potentially improve outcomes following transplantation.