The role of Core C is to provide mouse models to all research projects. We will pursue two specific aims.
Aim 1 includes: 1) coordinating, purchasing and housing immunodeficient (NOD/SCID and NOD/SCID/yc KO) mice, which will be used to prepare humanized mice (see Aim 2) for all projects (except Project 3, as explained in the Research Strategies section);and 2) maintaining and producing immunodeficient porcine cytokine transgenic mice. The porcine cytokine transgenic mice generated in this laboratory provide an excellent murine model for porcine hematopoietic stem/progenitor cell transplantation. These mice will be used to evaluate CD47 gene transduction in porcine hematopoietic progenitors (Project 2), and to prepare hu-mice for assessing human NK cell tolerance to porcine xenografts by mixed hematopoietic chimerism (Project 3).
Aim 2 is to provide humanized mouse (hu-mouse) models, including: 1) 'standard'hu-mice with a functional human immune system;2) hu-mice with porcine thymic grafts;3) transgenic hu-mice that express human CD39 transgenes, and 4) porcine chimeric hu-mice with porcine hematopoietic cells expressing a HLA-E/human B2m/peptide trimer. Our approach to generating hu-mice with a functional immune system is to transplant fetal thymus tissue (under renal capsule) and CD34+ hematopoietic stem/progenitor cells (i.v.) in immunodeficient mice. The 'standard'hu-mice will be used to test the immunoregulatory reagents/protocols to be used in non-human primates (Projects 1 and 2). The HLAE/ human p2m/peptide trimer-expressing porcine chimeric hu-mice will be used to assess the potential of NK cell inhibitory ligand expression on porcine cells to induce human NK cell tolerance in Project 3. Hu-mice with porcine thymic grafts and human CD39-overexpresing hu-mice will be used in Project 4 to investigate the role of CD39 in human regulatory T cell development in xenogeneic porcine thymic grafts. The core will prepare and validate the mouse models, and then either perform the proposed experiments (for Projects 1 and 2) or provide 'ready-to-use'models to the investigators (for Projects 3 and 4). As detailed in each research components, these mouse models are essential to the success of this program project.
RELEV/ NCE (See instructions): Xenotransplantation from pigs provides a possible solution to the over whelming scarcity of human organ donors that presents a major limiting factor in clinical transplantation, the best available therapy for end-stage organ failure. The goal of this core is to provide transgenic and humanized mouse models to the investigators of this program project for better understanding of the major barriers to clinical xenotransplantation.
|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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