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.
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.
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|Yamada, Kazuhiko; Tasaki, Masayuki; Sekijima, Mitsuhiro et al. (2014) Porcine cytomegalovirus infection is associated with early rejection of kidney grafts in a pig to baboon xenotransplantation model. Transplantation 98:411-8|
|Wang, Yuantao; Wang, Hui; Bronson, Roderick et al. (2014) Rapid dendritic cell activation and resistance to allotolerance induction in anti-CD154-treated mice receiving CD47-deficient donor-specific transfusion. Cell Transplant 23:355-63|
|Navarro-Alvarez, Nalu; Yang, Yong-Guang (2014) Lack of CD47 on donor hepatocytes promotes innate immune cell activation and graft loss: a potential barrier to hepatocyte xenotransplantation. Cell Transplant 23:345-54|
|Kalscheuer, Hannes; Onoe, Takashi; Dahmani, Alexander et al. (2014) Xenograft tolerance and immune function of human T cells developing in pig thymus xenografts. J Immunol 192:3442-50|
|Tasaki, Masayuki; Shimizu, Akira; Hanekamp, Isabel et al. (2014) Rituximab treatment prevents the early development of proteinuria following pig-to-baboon xeno-kidney transplantation. J Am Soc Nephrol 25:737-44|
|Tena, A; Kurtz, J; Leonard, D A et al. (2014) Transgenic expression of human CD47 markedly increases engraftment in a murine model of pig-to-human hematopoietic cell transplantation. Am J Transplant 14:2713-22|
|Scalea, Joseph R; Villani, Vincenzo; Gillon, Bradford C et al. (2014) Development of antidonor antibody directed toward non-major histocompatibility complex antigens in tolerant animals. Transplantation 98:514-9|
|Sekijima, Mitsuhiro; Waki, Shiori; Sahara, Hisashi et al. (2014) Results of life-supporting galactosyltransferase knockout kidneys in cynomolgus monkeys using two different sources of galactosyltransferase knockout Swine. Transplantation 98:419-26|
|Haspot, F; Li, H W; Lucas, C L et al. (2014) Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells. Am J Transplant 14:49-58|
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