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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI045897-12
Application #
8377266
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$329,761
Indirect Cost
$97,420
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Xia, Jinxing; Hu, Zheng; Yoshihara, Satoshi et al. (2016) Modeling Human Leukemia Immunotherapy in Humanized Mice. EBioMedicine 10:101-8
Zhang, Mingyou; Wang, Hui; Tan, Shulian et al. (2016) Donor CD47 controls T cell alloresponses and is required for tolerance induction following hepatocyte allotransplantation. Sci Rep 6:26839
Tena, Aseda A; Sachs, David H; Mallard, Christopher et al. (2016) Prolonged Survival of Pig Skin on Baboons After Administration of Pig Cells Expressing Human CD47. Transplantation :
Tasaki, Masayuki; Villani, Vincenzo; Shimizu, Akira et al. (2016) Role of bone marrow maturity, insulin-like growth factor 1 receptor and forkhead box protein N1 in thymic involution and rejuvenation. Am J Transplant :
Gao, Qi; Chen, Kexin; Gao, Lu et al. (2016) Thrombospondin-1 signaling through CD47 inhibits cell cycle progression and induces senescence in endothelial cells. Cell Death Dis 7:e2368
Buhler, L; Illigens, B M-W; Nadazdin, O et al. (2016) Persistence of Indirect but Not Direct T Cell Xenoresponses in Baboon Recipients of Pig Cell and Organ Transplants. Am J Transplant 16:1917-22

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