Transgenic strategies to overcome cellular rejection of pig-to-primate xenografts

• Antragsteller: Professor Dr. Jochen Seissler; Professor Dr. Eckhard Wolf
• Fachliche Zuordnung: Herz- und Gefäßchirurgie
• Förderung: Förderung von 2004 bis 2014
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5470814

Successful pig-to-primate organ transplantation requires complex genetic modifications of donor organs to prevent transplant rejection and physiological incompatibilities. To overcome hyperacute xenograft rejection (HAR) we intend to simultaneously overexpress human decay accelerating factor (DAF) and to knock-down a-1,3 galactosyltransferase (aGT) expression by small interfering RNA (siRNA) in transgenic pigs produced by a novel and highly efficient approach of lentiviral transgenesis. We have previously produced lines of transgenic pigs overexpressing human TNF a-related apoptosis-inducing ligand (TRAIL) or HLA-E alone or in combination with b2-microglobulin. Various strategies against HAR and cell-mediated rejection will be combined by crossing the respective pig lines, and effects on graft survival will be evaluated in pig-to-baboon transplantation experiments. Finally, a systematic screen for new targets in xenograft rejection will be performed by expression profiling in tissue samples from ex vivo perfused or transplanted pig organs (heart, kidney) at different time points after exposure to primate circulation. The scope of the latter experiments ranges from the discovery of new target molecules that are involved in xeno-rejection to the establishment of gene profile arrays that can be used to monitor the status of individual transplanted organs.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 535: Xenotransplantation
• Beteiligte Personen: Professor Dr. Nikolai Klymiuk; Dr. Annegret Wünsch