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Sustained function of genetically modified porcine lungs in an ex vivo model of pulmonary xenotransplantation
journal contribution
posted on 2013-11-01, 00:00 authored by Glen P Westall, Browyn J Levvey, Evelyn Salvaris, Julian Gooi, Sylvana Marasco, Frank Rosenfeldt, Chris Egan, Robin McEgan Ccp, Mark Mennen, Prue Russell, Simon C Robson, Mark B Nottle, Karen DwyerKaren Dwyer, Greg I Snell, Peter J CowanBACKGROUND: Xenotransplantation could provide a solution to the donor shortage that is currently the major barrier to solid-organ transplantation. The ability to breed pigs with multiple genetic modifications provides a unique opportunity to explore the immunologic challenges of pulmonary xenotransplantation. METHODS: Explanted lungs from wild-type and 3 groups of genetically modified pigs were studied: (i) α1,3-galactosyltransferase gene knockout (GTKO); (ii) GTKO pigs expressing the human complementary regulatory proteins CD55 and CD59 (GTKO/CD55-59); and (iii) GTKO pigs expressing both CD55-59 and CD39 (GTKO/CD55-59/CD39). The physiologic, immunologic and histologic properties of porcine lungs were evaluated on an ex vivo rig after perfusion with human blood. RESULTS: Lungs from genetically modified pigs demonstrated stable pulmonary vascular resistance and better oxygenation of the perfusate, and survived longer than wild-type lungs. Physiologic function was inversely correlated with the degree of platelet sequestration into the xenograft. Despite superior physiologic profiles, lungs from genetically modified pigs still showed evidence of intravascular thrombosis and coagulopathy after perfusion with human blood. CONCLUSIONS: The ability to breed pigs with multiple genetic modifications, and to evaluate lung physiology and histology in real-time on an ex vivo rig, represent significant advances toward better understanding the challenges inherent to pulmonary xenotransplantation.
History
Journal
Journal of heart and lung transplantationVolume
32Issue
11Pagination
1123 - 1130Publisher
ElsevierLocation
Amsterdam, The NetherlandsPublisher DOI
eISSN
1557-3117Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2013, International Society for Heart and Lung TransplantationUsage metrics
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Gal knockoutex vivo lung perfusiongenetically engineeredhyperacute rejectionlungswinexenotransplantationAnimalsAnimals, Genetically ModifiedAntigens, CDApyraseCD55 AntigensCD59 AntigensFemaleGalactosyltransferasesGene Knockout TechniquesHumansLung TransplantationMaleModels, AnimalPerfusionTransplantation, HeterologousVascular ResistanceScience & TechnologyLife Sciences & BiomedicineCardiac & Cardiovascular SystemsRespiratory SystemSurgeryTransplantationCardiovascular System & CardiologySWINE LUNGSHUMAN BLOODHUMAN CD39COMPLEMENTXENOGRAFTSMECHANISMSSURVIVALBABOONS
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