This is a renewal of a highly synergistic PPG exploring tolerance induction for xenotransplantation. Themes include: 1) Tolerance of the adaptive immune system; 2) Overcoming innate immune barriers; and 3) Using advanced genetic engineering techniques to improve genetically modified (GM) MGH inbred miniature swine. In Project 1, ?Achieving Xenograft Tolerance through Thymic Programming in Primates?, we will study and attempt to avoid the proteinuria which limits GalT-KO pig kidney transplant survival in baboons; we will optimize tolerance and protective immunity by transplanting a hybrid vascularized thymus (VT) containing pig and baboon TECs and combine this with mixed xenogeneic chimerism with intra-bone injection of pig bone marrow to simultaneously tolerize both adaptive and innate immunity. In Project 2, ?Achieving Xenograft Tolerance through Mixed Chimerism?, which also uses the pig-to-baboon model, we have achieved prolonged mixed chimerism in baboon recipients of human CD47 (hCD47) Tg pig hematopoietic cells (HCs), resulting in remarkably prolonged pig skin graft survival; we will combine this approach with intrabone injection of hCD47 Tg/hCD55 Tg/GalT KO pig hematopoietic cells and use ex-vivo expanded recipient Tregs to enhance engraftment, aiming to achieve more durable chimerism and, with it, tolerance of B, NK and T cells; we will also test HCs from new GM swine produced in Project 4. Project 3, ?Tolerance of Adaptive and Innate Human Anti-Pig Immune Responses in Humanized Mice?, combines mixed xenogeneic chimerism and porcine thymic transplantation in humanized mice with robust human immune systems; we will combine engineered pig/human hybrid thymi with mixed xenogeneic chimerism to achieve multi-faceted immune tolerance along with protective immunity for both human and porcine tissues; we will determine the impact of the hCD47 Tg on induction of porcine mixed chimerism in these mice and determine the impact of duration of this mixed chimerism on human T, B and NK cell tolerance. In Project 4, ?Improving Xenogeneic Chimerism and Tolerance through Genome Engineering Technology?, advanced genetic engineering techniques will be used to generate two optimal GM pig lines, one for tolerance induction and the other for organ transplantation, on a background of inbred miniature swine with common GMs that will be needed for both purposes. Core A will provide administrative support for the PPG, facilitating interactions between the primary and subcontract sites. Core B will support all large animal needs, including non-human primates and GM MGH inbred miniature swine; provide support for infectious diseases, coagulation and clotting issues of swine and baboons; and provide mAbs and antisera. The synergism of these projects and cores and the fertile interactions among them should bring us closer to the goal of clinical xenotransplantation.

Public Health Relevance

Overview Narrative This is a highly synergistic program project grant engaging multidisciplinary expertise in order to accelerate the advancement of xenotransplantation, the transplantation of organs from animals to humans, which is our best hope for overcoming the severe shortage of human organs for transplantation. We will use the most advanced genetic engineering techniques to rapidly modify miniature pigs that are close in size to humans and have been inbred for 40 years to provide a standardized, renewable source of organs for xenotransplantation. Animal models including rodents with robust human immune systems as well as non-human primates will use these genetically modified pigs in studies that will optimize immune tolerance induction to avoid graft rejection while assuring a well-functioning immune system and optimizing the function of transplanted pig organs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI045897-18
Application #
9544818
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Nabavi, Nasrin N
Project Start
2000-09-15
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
18
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Sykes, Megan (2018) IXA Honorary Member Lecture, 2017: The long and winding road to tolerance. Xenotransplantation 25:e12419
Proto, Jonathan D; Doran, Amanda C; Subramanian, Manikandan et al. (2018) Hypercholesterolemia induces T cell expansion in humanized immune mice. J Clin Invest 128:2370-2375
Chen, Mo; Wang, Yuantao; Wang, Hui et al. (2018) Elimination of donor CD47 protects against vascularized allograft rejection in mice. Xenotransplantation :e12459
Watanabe, Hironosuke; Sahara, Hisashi; Nomura, Shunichiro et al. (2018) GalT-KO pig lungs are highly susceptible to acute vascular rejection in baboons, which may be mitigated by transgenic expression of hCD47 on porcine blood vessels. Xenotransplantation 25:e12391
Sachs, David H (2018) Transplantation tolerance through mixed chimerism: From allo to xeno. Xenotransplantation 25:e12420
Fishman, Jay A; Sachs, David H; Yamada, Kazuhiko et al. (2018) Absence of interaction between porcine endogenous retrovirus and porcine cytomegalovirus in pig-to-baboon renal xenotransplantation in vivo. Xenotransplantation 25:e12395
Mastroianni, Melissa; Ng, Zhi Yang; Goyal, Ritu et al. (2018) Topical Delivery of Immunosuppression to Prolong Xenogeneic and Allogeneic Split-Thickness Skin Graft Survival. J Burn Care Res 39:363-373
Yamada, Kazuhiko; Shah, Jigesh A; Tanabe, Tatsu et al. (2017) Xenotransplantation: Where Are We with Potential Kidney Recipients? Recent Progress and Potential Future Clinical Trials. Curr Transplant Rep 4:101-109
Chen, Bing; Fan, Wei; Zou, Jun et al. (2017) Complement Depletion Improves Human Red Blood Cell Reconstitution in Immunodeficient Mice. Stem Cell Reports 9:1034-1042
Tena, Aseda A; Sachs, David H; Mallard, Christopher et al. (2017) Prolonged Survival of Pig Skin on Baboons After Administration of Pig Cells Expressing Human CD47. Transplantation 101:316-321

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