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.
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.
|Peraino, Jaclyn Stromp; Zhang, Huiping; Rajasekera, Priyani V et al. (2014) Diphtheria toxin-based bivalent human IL-2 fusion toxin with improved efficacy for targeting human CD25(+) cells. J Immunol Methods 405:57-66|
|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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