All Studies will be carried out using GalTKO.CD46CD55 pigs (designated GE pigs) with additional genetic modifications. Project 1: Effect of genetic modifications on pig heart and kidney graft survival in baboons.
Aim 1 : To investigate the efficacy in baboons of a clinically-applicable immunosuppressive regimen in preventing the innate and adaptive immune responses after heterotopic heart transplantation (Tx) from (A) GE pigs and (B) GE/CIITA pigs, and to determine whether prevention of elicited xenoimmunity correlates with delay in the onset or prevention of coagulation dysfunction.
Aim 2 : To investigate the coagulation disorders that develop after (A) heterotopic heart Tx (n=6) or (B) life-supporting kidney Tx (n=6) from GE/CIITA pigs additionally transgenic for human thrombomodulin (TBM) in baboons immunosuppressed with a clinically-applicable regimen, and to determine the causes of graft failure and coagulation dysfunction.
Aim 3 : To investigate the coagulation disorders that develop after (A) heterotopic heart Tx (n=6) or (B) life-supporting kidney Tx (n=6) from GE/CIITA/TBM pigs additionally transgenic for human endothelial cell protein C receptor (EPCR) in baboons immunosuppressed with a clinically-applicable regimen, and to determine the causes of graft failure and coagulation dysfunction. Project 2: Coagulation control to protect GalTKO lung and liver xenografts:
Aim 1 : Determine whether platelet sequestration by a GE lung xenograft is caused by GP1B/vWF interaction, glycoprotein desialylation, or a combination of both mechanisms.
Aim 2 : Establish whether molecular incompatibilities between porcine TBM or EPCR and their human blood substrates amplify coagulation pathway activation by GE pig lung.
Aim3 : Evaluate life supporting performance of lung and liver xenografts in baboons based on optimal pig phenotype and pharmacologic interventions as identified in the first two aims. Core A (Pig Core):
Aim 1 : Production and supply of genetically-engineered pigs as a source of heart, kidney, liver and lung, in sufficient numbers to meet the goals of Projects 1 and 2.
Aim 2 : Production and supply of genetically-engineered pigs on the GE/CIITA genetic background which additionally express the transgene, TBM and/or EPCR, as a means to modulate thrombosis and coagulopathy associated with organ xenotransplantation. Core B (Administrative Core): Will facilitate and coordinate communications between the members of the Consortium themselves and between them and the 4 members of the Scientific Advisory Board, all of whom will be Consultants to the Consortium.
There is a critical shortage of organs from deceased humans for purposes of transplantation. The proposed studies are directed towards resolving this problem by exploring and overcoming the remaining barriers that currently prevent pig organs from being transplanted successfully into patients with end-stage organ (heart, kidney, lung, liver) failure. It is anticipated that these barriers can be overcome by the use of organs from unique genetically-engineered pigs and novel reagents.
|Harris, Donald G; Quinn, Kevin J; French, Beth M et al. (2015) Meta-analysis of the independent and cumulative effects of multiple genetic modifications on pig lung xenograft performance during ex vivo perfusion with human blood. Xenotransplantation 22:102-11|
|Wijkstrom, Martin; Bottino, Rita; Iwase, Hayoto et al. (2015) Glucose metabolism in pigs expressing human genes under an insulin promoter. Xenotransplantation 22:70-9|
|Ezzelarab, Mohamed B; Ekser, Burcin; Azimzadeh, Agnes et al. (2015) Systemic inflammation in xenograft recipients precedes activation of coagulation. Xenotransplantation 22:32-47|
|Nagaraju, Santosh; Bertera, Suzanne; Funair, Amber et al. (2014) Streptozotocin-associated lymphopenia in cynomolgus monkeys. Islets 6:e944441|
|Iwase, Hayato; Ekser, Burcin; Hara, Hidetaka et al. (2014) Regulation of human platelet aggregation by genetically modified pig endothelial cells and thrombin inhibition. Xenotransplantation 21:72-83|
|Burdorf, L; Stoddard, T; Zhang, T et al. (2014) Expression of human CD46 modulates inflammation associated with GalTKO lung xenograft injury. Am J Transplant 14:1084-95|
|Cowan, Peter J; Cooper, David K C; d'Apice, Anthony J F (2014) Kidney xenotransplantation. Kidney Int 85:265-75|
|Li, Jiang; Ezzelarab, Mohamed B; Ayares, David et al. (2014) The potential role of genetically-modified pig mesenchymal stromal cells in xenotransplantation. Stem Cell Rev 10:79-85|
|LaMattina, John C; Burdorf, Lars; Zhang, Tianshu et al. (2014) Pig-to-baboon liver xenoperfusion utilizing GalTKO.hCD46 pigs and glycoprotein Ib blockade. Xenotransplantation 21:274-86|
|Zhou, Huidong; Iwase, Hayato; Wolf, Roman F et al. (2014) Are there advantages in the use of specific pathogen-free baboons in pig organ xenotransplantation models? Xenotransplantation 21:287-90|
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