The Immunomodulatory Potential of Normothermic Liver Perfusion: Reconditioning the Graft's Immune Profile Before Transplantation

Abstract

Normothermic machine perfusion (NMP) has emerged as a promising technique in liver transplantation, addressing limitations of static cold storage by preserving organs under near-physiological conditions. Beyond its known benefits in viability  
assessment and reduction of ischemia-reperfusion injury, recent evidence highlights its immunomodulatory potential. This review explores the evolving role of NMP as a dynamic immunological platform capable of reconditioning donor liver immune 
profiles before transplantation. The liver harbors a rich network of innate and adaptive immune cells, including Kupffer cells, dendritic cells, T cells, and liver sinusoidal endothelial cells (LSECs), all of which contribute to early allograft injury and long-term rejection. The controlled ex vivo environment of NMP provides a unique opportunity to intervene therapeutically by flushing inflammatory mediators, replenishing anti-inflammatory agents, or delivering gene therapies directly to the graft. By altering the immune milieu prior to implantation, NMP could reduce early allograft dysfunction and chronic rejection, while improving recipient immune tolerance. We detail the mechanistic pathways involved in graft immune modulation during NMP, including cytokine clearance, cellular reprogramming, and targeted immunotherapy. We also evaluate the feasibility of interventions such as mesenchymal stem cell delivery, anti-inflammatory agents, and extracellular vesicle therapy during perfusion. Challenges including graft-specific immune profiling, therapeutic delivery logistics, and clinical translation are critically analyzed.