Xenotransplantation may be clinically feasible once the molecular barriers between species and mechanisms of graft loss or rejection are better understood. Xenograft survival would have to be also achieved without compromising the recipient to the extent that systemic toxicity would be encountered. In this regard, genetic engineering of swine, with xenograft modification to provide greater compatibility, has been of recent interest. Thrombotic and inflammatory reactions to porcine bone marrow (BM)-derived cells, infused pancreatic islets and the vasculature of organ grafts are linked to the difficulties in establishing mixed discordant chimerism, pancreatic islet-associated procoagulant injury and the development of xenograft microangiopathy. These responses are likely associated with humoral immune reactions to xenogeneic tissues. However, thrombotic processes with progressive xenograft vascular injury and infarction may be further exacerbated by documented intrinsic molecular incompatibilities in regulation of blood clotting between discordant species. An example of this would be the failure of natural porcine anticoagulants, such as thrombomodulin, to interact with human/primate coagulation factors, such as thrombin and Protein C. The development of the GalT-KO pig and consequent removal of the dominant xeno-antigen have been a major advance in xenotransplantation research. However, problems still persist in inducing tolerance by generating mixed xenogeneic chimerism, either by vascularized thymic tissues or the BM-derived cell approach in baboons. GalT-KO islets have not yet been tested but the current GalT-KO renal and cardiac xenograft limited survival times and associated vascular injury patterns still preclude clinical application. The goals of this application are to effectively manage graft thrombotic and vascular sequelae associated with GalT-KO pig-to-baboon renal grafting and those complications seen in islet xenotransplantation. We will evaluate transgenic approaches to over-express CD39, a key thromboregulatory protein and/or thrombomodulin in pigs. Transgenic porcine vascularized renal grafts and pancreatic islets over-expressing these human factors will be transplanted into baboons. Our strategies will include optimal immunosuppressive interventions with protocols to attempt induction of tolerance. These studies will be judged successful if novel, clinically relevant antithrombotic therapies can be then developed and applied. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI066331-02
Application #
7086952
Study Section
Special Emphasis Panel (ZAI1-MP-I (M1))
Program Officer
Koh, Crystal Y
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$595,760
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Schmelzle, Moritz; Duhme, Constanze; Junger, Wolfgang et al. (2013) CD39 modulates hematopoietic stem cell recruitment and promotes liver regeneration in mice and humans after partial hepatectomy. Ann Surg 257:693-701
Ekser, Burcin; Bianchi, John; Ball, Suyapa et al. (2012) Comparison of hematologic, biochemical, and coagulation parameters in ?1,3-galactosyltransferase gene-knockout pigs, wild-type pigs, and four primate species. Xenotransplantation 19:342-54

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