The Large Animal Core will provide the facilities, management and technical expertise needed to supply MGH miniature swine and baboons and tissue samples for all projects of the proposed program as well as expert veterinary care, immunological reagents, and microbiologic diagnostic assays and support. Clinical samples will be distributed to maximize utilization of each animal for studies of clinically relevant regimens for xenotransplantation. The success of each component of this program is dependent on the quality, predictability, and accessibility of the animals, microbiologic support, and antibodies provided by this Core. Animal care is reviewed weekly at meetings of the principal investigators and the veterinary staff.
The Aims of the Large Animal Core include:
Aim 1 : Production, quality control, tracking, and maintenance of MGH MHC inbred miniature swine including the novel MGH GalT-KO swine, with homozygous disruption of the a-1,3-galactosyltransferase gene (see Figures 1 and 2) and the GalT-KO-CD39 transgenic swine. Miniature swine production is monitored using a computerized, web-based system developed to coordinate the breeding, quality control, allocation, transportation and utilization of animals for each Project. Significant improvements in swine production have achieved an increased supply of swine adequate to the proposed studies.
Aim 2 : Purchase and maintenance of non-human primates Aim 3: Infectious Disease/Microbiology support for immunocompromised animals to provide molecular diagnostic assays for viral pathogens and advice on infectious disease management.
Aim 4 : Production, characterization, and maintenance of a unique series of monoclonal antibodies (MAb)reactive with swine and baboon cell surtace antigens to assess pig and baboon cell lineages and improve cellular depletion. Coordination of these activities is performed by Scott Arn, who directs all aspects of the development of the knockout swine, the provision of primates and maintenance of the detailed database used by all investigators of the Transplantation Biology Research Center at MGH. Dr. Jay Fishman will oversee infectious disease management and microbiologic diagnostics in xenotransplantation studies. Animal procedures are conducted by experienced transplant surgeons, veterinary clinicians and anesthesiologists in dedicated sterile operating rooms to optimize care and comfort.

Public Health Relevance

Knockout swine/tissues (Projects 1,2,3,4) and baboons (1,2,4), antibody reagents, and microbiologic diagnostics and prophylaxis provided by this core are essential to each of the proposed projects. Viral diagnostics and reagents for LCMV will be provided to Project 3. MAb are used in studies of swine cell lineages of pig thymus tissue (Project 1,3), in baboons (Projects 2), and in studies of thromboregulation (Project 4). T cell-specific diphtheria toxin-conjugated Mabs are used to deplete lymphocyte populations in baboons as part ofthe recipient conditioning regimens in Projects 1 and 2.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI045897-14
Application #
8688879
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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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