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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090959-03
Application #
8309417
Study Section
Special Emphasis Panel (ZAI1-JBS-I (M1))
Program Officer
Nabavi, Nasrin N
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$1,530,066
Indirect Cost
$195,345
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Iwase, Hayato; Ekser, Burcin; Hara, Hidetaka et al. (2016) Thyroid hormone: relevance to xenotransplantation. Xenotransplantation 23:293-9
Cooper, David K C; Matsumoto, Shinichi; Abalovich, Adrian et al. (2016) Progress in Clinical Encapsulated Islet Xenotransplantation. Transplantation 100:2301-2308
Murthy, Raghav; Bajona, Pietro; Bhama, Jay K et al. (2016) Heart Xenotransplantation: Historical Background, Experimental Progress, and Clinical Prospects. Ann Thorac Surg 101:1605-13
Wijkstrom, Martin; Iwase, Hayato; Paris, Wayne et al. (2016) Renal xenotransplantation: experimental progress and clinical prospects. Kidney Int :
Lee, Whayoung; Hara, Hidetaka; Ezzelarab, Mohamed B et al. (2016) Initial in vitro studies on tissues and cells from GTKO/CD46/NeuGcKO pigs. Xenotransplantation 23:137-50
Cooper, David K C (2016) Modifying the sugar icing on the transplantation cake. Glycobiology 26:571-81
Cooper, David K C; Wijkstrom, Martin; Hariharan, Sundaram et al. (2016) Selection of Patients for Initial Clinical Trials of Solid Organ Xenotransplantation. Transplantation :
Cooper, David K C; Ekser, Burcin; Ramsoondar, Jagdeece et al. (2016) The role of genetically engineered pigs in xenotransplantation research. J Pathol 238:288-99
Cooper, David K C; Dou, Ke-Feng; Tao, Kai-Shan et al. (2016) Pig Liver Xenotransplantation: A Review of Progress Toward the Clinic. Transplantation 100:2039-47

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