Hyperacute rejection ofthe heart and kidney is reliably prevented when GalTKO organs are used that additionally express a human complement pathway regulatory protein (hCPRP). In contrast, although GalTKO.hCPRP pig lung xenograft function is significantly prolonged relative to GalTKO or hCPRP lungs, lung injury nonetheless occurs within hours of transplantation into baboons or following perfusion with human blood. Similarly, platelet sequestration occurs almost immediately when GalTKO.hCPRP pig livers are orthotopically transplanted in baboons, and limits recipient survival. A number of molecular incompatibilities between pig endothelial membrane glycoproteins and primate platelet receptors and plasma coagulation pathway proteins probably explain the mechanistic basis of coagulation pathway dysregulation and platelet sequestration in lung and liver xenograft injury. These incompatibilities may also contribute to related problems in heart and kidney xenotransplants, thrombotic microangiopathy (TM) and consumptive coagulopathy (CC). In this Project we will take advantage ofthe GalTKO.hCPRP pig lung's particular avidity for platelet and neutrophil sequestration, and its propensity to amplify coagulation pathway activation. Using a combination of clinically available approaches to impact thromboregulation (DDAVP, to deplete donor vWF pretransplant;zanamivir, a sialydase inhibitor, to maintain sialic acid expression on circulating platelet receptors and associated vWF) and unique molecular targeting reagents (an anti-GPlB Fab and an antisialydase antibody), Aim 1 will test the hypothesis that GPlB/vWF, modulated by desialydation, mediate primate platelet and neutrophil sequestration by porcine endothelium.
In Aim 2, GalTKO.hCPRP pig lungs that also express human thrombin pathway regulatory proteins (thrombomodulin or endothelial protein C receptor) will reveal whether molecular incompatibilities in this pathway contribute significantly to lung injury, and whether expression of these molecules is protective.
Aim 3 will determine whether strategies arising from Aims 1 and 2 will consistently yield life-supporting function of a pig lung in a baboon, and whether a similar approach reliably prevents thrombocytopenia in a baboon supported by a GalTKO.hCPRP pig liver.

Public Health Relevance

This Project is likely to improve understanding of mechanisms of platelet sequestration, coagulation cascade activation, and organ xenograft injury that are probably relevant to lung and liver, and quite possibly to heart and kidney xenografts. By identifying a clinically applicable approach to prevent these phenomena, clinical application of pig liver xenografts as a bridge-to-allotransplant may result as well as progress to control TM and CC in Project 1.

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 #
8514497
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
$624,522
Indirect Cost
$95,601
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Jagdale, Abhijit; Iwase, Hayato; Klein, Edwin et al. (2018) Will donor-derived neoplasia be problematic after clinical pig organ or cell xenotransplantation? Xenotransplantation :e12469
Zhang, Zhongqiang; Hara, Hidetaka; Long, Cassandra et al. (2018) Immune Responses of HLA Highly Sensitized and Nonsensitized Patients to Genetically Engineered Pig Cells. Transplantation 102:e195-e204
French, Beth M; Sendil, Selin; Sepuru, Krishna Mohan et al. (2018) Interleukin-8 mediates neutrophil-endothelial interactions in pig-to-human xenogeneic models. Xenotransplantation 25:e12385
Yamamoto, Takayuki; Iwase, Hayato; King, Timothy W et al. (2018) Skin xenotransplantation: Historical review and clinical potential. Burns 44:1738-1749
Li, Qi; Hara, Hidetaka; Zhang, Zhongqiang et al. (2018) Is sensitization to pig antigens detrimental to subsequent allotransplantation? Xenotransplantation 25:e12393
Laird, Christopher T; Hassanein, Wessam; O'Neill, Natalie A et al. (2018) P- and E-selectin receptor antagonism prevents human leukocyte adhesion to activated porcine endothelial monolayers and attenuates porcine endothelial damage. Xenotransplantation 25:e12381
Zhang, Guoqiang; Hara, Hidetaka; Yamamoto, Takayuki et al. (2018) Serum amyloid a as an indicator of impending xenograft failure: Experimental studies. Int J Surg 60:283-290
Jagdale, Abhijit; Cooper, David K C; Iwase, Hayato et al. (2018) Chronic dialysis in patients with end-stage renal disease: Relevance to kidney xenotransplantation. Xenotransplantation :e12471
Iwase, Hayato; Yamamoto, Takayuki; Cooper, David K C (2018) Episodes of hypovolemia/dehydration in baboons with pig kidney transplants: A new syndrome of clinical importance? Xenotransplantation :e12472

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