Introduction: Liver transplantation continues to face challenges of acute and chronic rejection, especially in xenotransplantation where interspecies immune barriers are profound. Polyamines—putrescine, spermidine, and spermine—are emerging as key regulators of immune responses, oxidative stress, and tissue regeneration. While their cytoprotective and immunomodulatory roles have been explored in oncology and aging, their application in transplant immunology remains largely untapped.
Methods: We propose a translational xenotransplantation model using porcine liver grafts to investigate polyamine dynamics during immune activation. The study will quantify tissue-specific and systemic polyamine levels during acute rejection and tolerance phases. Targeted interventions-such as dietary spermidine supplementation or modulation of polyamine-metabolizing enzymes-will be evaluated as adjuncts to standard immunosuppression. Molecular assays including cytokine profiling, regulatory T-cell quantification, and hepatocyte autophagy markers will be used to determine immunologic impact.
Results: Preclinical data indicate that elevated spermidine levels are associated with enhanced graft tolerance and decreased oxidative injury during liver ischemia-reperfusion. Initial findings from cardiac and renal xenografts also support the hypothesis that polyamines modulate cross-species immune responses. We anticipate that polyamine supplementation may reduce pro-inflammatory cytokine release, increase Treg populations, and promote hepatocyte regeneration, resulting in prolonged xenograft survival.
Conclusion: By integrating polyamine profiling with surgical and molecular innovation, this project positions polyamines as both biomarkers and therapeutic agents in transplantation. Their selective immunomodulatory action offers a potential paradigm shift from broad immunosuppression to metabolic immunoregulation. This approach could improve xenograft acceptance, reduce drug toxicity, and enhance long-term transplant outcomes, particularly in low-resource settings aiming to expand xenotransplantation programs.