Xenotransplantation will only become clinically feasible once mechanisms of xenograft loss and rejection are better understood. The development of inbred miniature GalT-KO swine with removal of the dominant xeno-antigen has been a major advance. However, problems still persist in generating mixed xenogeneic chimerism in baboons and obtaining tolerance to xenogeneic cells and vascularized xenografts. Inflammatory reactions to porcine bone marrow-derived cells and the vasculature of organ grafts are linked to aberrant immune responses, together with procoagulant activation and the development of xenograft microvascular injury. Thrombotic processes and the progressive xenograft microangiopathy appear exacerbated by dysfunctional immune reactions and already documented intrinsic molecular incompatibilities in thromboregulation between discordant species. We have made significant progress in defining mechanisms of consumptive coagulopathy linked to associated functional incompatibilities of CD39 and thrombomodulin across species, and by determining novel vascular markers of injury associated with humoral rejection. We have recently shown that CD39 is expressed by the endothelium and also by T regulatory cells. Hence, adenosine generated by this ectonucleotidase blocks platelet activation impeding coagulation and also serves as an immune suppressive mediator. Our new studies will build on these successes and insights to address the following Specific Aims: #1: Study how cellular immune mechanisms and adenosine production by CD39 expressed by T regulatory cells impact xenogeneic tolerance mechanisms (with models developed in Project 3);and #2: Demonstrate therapeutic potential of transgenic upregulation of human CD39 and thrombomodulin in GalT-KO swine in thymokidney xenotransplant and tolerance models (in Projects 1 and 2). These strategies will include optimal immunosuppressive interventions with protocols to attempt induction of tolerance and ameliorate vascular inflammation in baboons. The overall goals of this application will be to effectively manage immune reactions, graft vascular Injury and thrombosis, currently associated with GalT-KO pig-to-baboon thymokidney xenotransplantation, and thereby provide clinically relevant survival times.

Public Health Relevance

The overall goal of this project is to limit xenograft injury and promote tolerance by targeting common mediators of vascular inflammation, innate and adaptive immunity. These studies will provide important insights into the roles of extracellular nucleotides as inflammatory or immune mediators and will also integrate understanding of the mechanisms of coagulation, platelet and T cell activation in the rejection of transplanted organs. If successful, this approach will bring xenotransplantation closer to clinical application and provide insights into the regulation of thrombosis and vascular injury within transplanted organs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-QV-I)
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Massachusetts General Hospital
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Takenaka, Maisa C; Robson, Simon; Quintana, Francisco J (2016) Regulation of the T Cell Response by CD39. Trends Immunol 37:427-39
Am Esch, Jan Schulte; Schmelzle, Moritz; Duhme, Constanze et al. (2016) Reply to Letter: ""Infusion of CD133+ Bone Marrow-Derived Stem Cell After Selective Portal Vein Embolization Enhances Functional Hepatic Reserves After Extended Right Hepatectomy"". Ann Surg 263:e44-5
Hu, Zheng; Xia, Jinxing; Fan, Wei et al. (2016) Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice. Oncotarget 7:6448-59
Lazar, Zsofia; Müllner, Nina; Lucattelli, Monica et al. (2016) NTPDase1/CD39 and aberrant purinergic signalling in the pathogenesis of COPD. Eur Respir J 47:254-63
Xia, Jinxing; Hu, Zheng; Yoshihara, Satoshi et al. (2016) Modeling Human Leukemia Immunotherapy in Humanized Mice. EBioMedicine 10:101-8
Zhang, Mingyou; Wang, Hui; Tan, Shulian et al. (2016) Donor CD47 controls T cell alloresponses and is required for tolerance induction following hepatocyte allotransplantation. Sci Rep 6:26839
Tena, Aseda A; Sachs, David H; Mallard, Christopher et al. (2016) Prolonged Survival of Pig Skin on Baboons After Administration of Pig Cells Expressing Human CD47. Transplantation :
Tasaki, Masayuki; Villani, Vincenzo; Shimizu, Akira et al. (2016) Role of bone marrow maturity, insulin-like growth factor 1 receptor and forkhead box protein N1 in thymic involution and rejuvenation. Am J Transplant :
Gao, Qi; Chen, Kexin; Gao, Lu et al. (2016) Thrombospondin-1 signaling through CD47 inhibits cell cycle progression and induces senescence in endothelial cells. Cell Death Dis 7:e2368
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

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