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 #
5U19AI090959-02
Application #
8116016
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
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$1,544,173
Indirect Cost
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; Liu, Hong; Li, Tao et al. (2017) Therapeutic regulation of systemic inflammation in xenograft recipients. Xenotransplantation 24:
Laird, Christopher T; Burdorf, Lars; French, Beth M et al. (2017) Transgenic expression of human leukocyte antigen-E attenuates GalKO.hCD46 porcine lung xenograft injury. Xenotransplantation 24:
Bottino, Rita; Knoll, Michael F; Graeme-Wilson, Joshua et al. (2017) Safe use of anti-CD154 monoclonal antibody in pig islet xenotransplantation in monkeys. Xenotransplantation 24:
Iwase, Hayato; Hara, Hidetaka; Ezzelarab, Mohamed et al. (2017) Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts. Xenotransplantation 24:
Gao, Bingsi; Long, Cassandra; Lee, Whayoung et al. (2017) Anti-Neu5Gc and anti-non-Neu5Gc antibodies in healthy humans. PLoS One 12:e0180768
Iwase, Hayato; Liu, Hong; Schmelzer, Eva et al. (2017) Transplantation of hepatocytes from genetically engineered pigs into baboons. Xenotransplantation 24:
Zhang, Zhongqiang; Hara, Hidetaka; Long, Cassandra et al. (2017) IMMUNE RESPONSES OF HLA-HIGHLY-SENSITIZED AND NONSENSITIZED PATIENTS TO GENETICALLY-ENGINEERED PIG CELLS. Transplantation :
Lee, Whayoung; Mammen, Alex; Dhaliwal, Deepinder K et al. (2017) Development of retrocorneal membrane following pig-to-monkey penetrating keratoplasty. Xenotransplantation 24:

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