Xenotransplantation remains the best near-term hope for alleviating the critical shortage of allogeneic organs. A major advance in organ xenograft survival has been the development of a knock-out strain of miniature swine (GalT-KO), which are not subject to the severe rejection previously caused by natural anti- Gal antibodies. Our initial studies using these animals as donors demonstrated a marked improvement in the survival of life-supporting renal transplants when recipient baboons were treated with a regimen designed to induce T cell tolerance, as compared to relying on chronic immunosuppression. During this project period, we have expanded our studies of tolerance induction across the pig-to-baboon barrier and have achieved specific loss of primate anti-pig reactivity in several protocols, supporting the feasibility of tolerance induction. Nevertheless, significant problems remain before xenotransplantation will be applicable clinically. This resubmission application combines four component projects that encompass the most pressing problems and the most promising approaches in this field of research: 1) tolerance induction through vascularized thymic transplantation;2) tolerance induction through mixed chimerism;3) modeling of tolerance in mice with human immune systems;and 4) thromboregulatory barriers to xenotransplantation. All of these projects are highly interactive, and utilize numerous shared resources, many of which will be made available through the large and small animal cores. The work will be carried out in a unique environment, which provides interactions among scientists working in basic and cellular immunology as well as with clinicians committed to taking new therapies to clinical applications.
Xenotransplantation remains the best near-term hope for alleviating the critical shortage of allogeneic organs today. This Program Project grant combines four component projects that encompass what we consider to be the most pressing problems and the most promising approaches in this field of research.
|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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