The proposed studies are directed towards resolving two inter-related current problems in pig-tononhuman primate (NHP) organ xenotransplantation using GTKO.CD46.CD55 pigs (designated GE pigs) (i) to identify a clinically-applicable regimen that prevents an adaptive immune response, and (ii) to identify a means of preventing coagulation dysfunction - in the form of thrombocytopenia and/or consumptive coagulopathy (CC) with associated thrombotic microangiopathy. The immune response may influence the development of coagulation disorders, and coagulation dysregulation may influence the immune response. The exact causative factors of CC remain uncertain, but (i) heightened innate immunity (antibody, complement, platelets, macrophages, NK cells), (ii) the adaptive immune response (T and B cells), and (iii) molecular incompatibilities between pig and NHP, may all play roles. Graft vascular heterogeneity may also be evident as CC and thrombocytopenia occur more rapidly in NHPs with pig kidney rather than heart grafts. We propose that genetic modifications in pigs and novel therapies may protect against these factors. We shall use CIITA mutant pigs (with knock-down of SLA Class II) and other pigs transgenic for human thromboregulatory factors on the GTKO background.
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 Tx from (A) GE pigs (n=6) and (B) GE.CIITA pigs (n=6), and to determine whether prevention of elicited xenogeneic immunity correlates with delay in

Public Health Relevance

The proposed studies should provide a clinically-applicable immunosuppressive regimen, and elucidate the efficacy of the expression of human TBM and/or EPCR on pig endothelial cells in preventing the coagulation dysfunction seen following pig heart and kidney Tx in NHPs. The studies should throw light on the remaining barriers that need to be overcome, and indicate what further genetic modifications of the organ-source pig might be advantageous.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090959-04
Application #
8514496
Study Section
Special Emphasis Panel (ZAI1-JBS-I)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$567,587
Indirect Cost
$67,780
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Buhler, L; Illigens, B M-W; Nadazdin, O et al. (2016) Persistence of Indirect but Not Direct T Cell Xenoresponses in Baboon Recipients of Pig Cell and Organ Transplants. Am J Transplant 16:1917-22
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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