ABSTRACT Corneal transplantation is an effective sight‐restoring procedure, yet its global impact remains constrained by limited and uneven access to human donor tissue and by immune‐mediated graft failure, particularly in high‐risk recipients. Xenotransplantation offers a potentially scalable alternative, but successful clinical translation requires an understanding of how xenogeneic immune responses differ from, and build upon, the mechanisms governing corneal allograft rejection. This review critically examines the immunologic lessons from corneal allotransplantation that are most relevant to xenograft development and evaluates current evidence for porcine corneal xenotransplantation. We focus on the conditional nature of corneal immune privilege, antigen‐recognition pathways, and the relationship between donor tissue burden and immune exposure. Particular emphasis is placed on fresh cellular porcine corneal xenotransplantation and non‐human primate studies, which demonstrate that prolonged graft survival is achievable but remains dependent on control of T‐cell responses, antibody production, complement activation, and macrophage‐mediated injury. Porcine corneal xenoantigens, including α‐Gal and non‐Gal epitopes, further distinguish xenogeneic from allogeneic transplantation. Emerging strategies include genetically engineered donor pigs, targeted immunosuppression and costimulation blockade, tissue‐selective lamellar and endothelial xenografts, and decellularized or hybrid constructs designed to reduce xenogeneic antigenic burden. Collectively, current evidence suggests that clinical corneal xenotransplantation is unlikely to depend on a single strategy. Rather, durable and scalable graft survival will likely require an indication‐specific combination of donor modification, immune modulation, and graft design. Lessons from corneal allotransplantation therefore provide an important framework for determining which immune barriers can be reduced through tissue selection and which remain unique to the cross‐species setting.
Introduction C-reactive protein (CRP) is a widely used inflammatory biomarker. We evaluated CRP alongside tissue injury markers in non-human primate (NHP) models of kidney and heart allo- and xeno-transplantation to assess CRP's sensitivity in detecting graft-specific inflammatory responses (acute rejection), and explored CRP elevations in the absence of clinically evident graft injury. A secondary objective compared CRP dynamics between NHP species. Methods Forty-two baboon or cynomolgus monkey NHPs received kidney (n = 12) or heart (n = 7) xenografts, or kidney (n = 12) or heart (n = 11) allografts. In serum obtained before transplant, after graft revascularization on the day of transplant, and at defined post-operative intervals, CRP, creatinine (kidney), and troponin-I (heart) were measured and correlated with clinical events and histopathology. Results Baboons exhibited higher baseline and pre-transplant CRP levels than cynomolgus monkeys (p < 0.05). Following kidney xenotransplantation, CRP rose to higher levels in baboons than cynomolgus monkeys (p < 0.05). In association with episodes of histologically confirmed graft rejection, CRP elevations preceded rises in creatinine (kidney) or troponin-I (heart) by 7-14 days. Additionally, CRP elaboration was observed in association with opportunistic infection and surgical procedures such as graft biopsies. Conclusion As reflected by CRP dynamics, systemic inflammation is associated with organ allo- and xenotransplantation in NHPs. We conclude that CRP is a potentially valuable marker of inflammation that, when interpreted alongside organ-specific biomarkers, quantifies the severity of immune activation associated with graft injury and detects additional inflammatory events, which may be clinically occult but influence experimental outcomes. CRP could be a valuable biometric adjunct in multi-parametric inflammation monitoring in transplantation and other disease models.
The shortage of donor livers motivates the development of pig-to-non-human-primate liver xenotransplantation. While gene-editing-mediated xenoantigen knockout reliably prevents hyperacute rejection (HAR), nevertheless, the integrated in-vivo phenotype and coagulation-associated complications of multi-gene-edited porcine livers remain poorly characterized. To address this knowledge gap, we established orthotopic auxiliary partial liver xenotransplantation in non-human primates using 6-, 8-, and 10-gene-edited porcine donors, and performed multi-modal longitudinal phenotyping covering graft function assessment, immune-coagulation profiling, PERV/PCMV DNA screening, as well as mechanistic analyses of graft injury. Consistent with prior reports, all three transplantations succeeded; xenoantigen knockout prevented HAR, and grafts maintained basal function with only mild sinusoidal congestion and limited complement-antibody deposition. Strikingly, every recipient developed severe thrombocytopenia, graft thrombosis, and thrombotic microangiopathy, which ultimately culminated in graft dysfunction. Further analyses revealed that aberrant endothelial ASGR1 and vWF expression together with porcine macrophage-mediated platelet clearance constituted principal drivers of platelet depletion; meanwhile, PERV and PCMV DNA were undetectable in recipient tissues. Collectively, although xenoantigen knockout effectively averts HAR, irreversible coagulation-cascade activation, thrombosis and consumptive coagulopathy still represent the principal barriers to long-term xenograft survival even in the setting of donor-expressed human anticoagulant transgenes hTBM, hCD39, and hEPCR. These findings provide valuable insights for future donor-engineering and complication-intervention strategies.
