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

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 #
7P01AI045897-15
Application #
8871642
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
2016-08-18
Budget Start
2015-07-01
Budget End
2016-08-18
Support Year
15
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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
Holzer, Paul W; Leonard, David A; Shanmugarajah, Kumaran et al. (2017) A Comparative Examination of the Clinical Outcome and Histological Appearance of Cryopreserved and Fresh Split-Thickness Skin Grafts. J Burn Care Res 38:e55-e61
Jin, Feng; He, Jin; Jin, Chunhui et al. (2017) Antithymocyte globulin treatment at the time of transplantation impairs donor hematopoietic stem cell engraftment. Cell Mol Immunol 14:443-450
Zuber, Julien; Sykes, Megan (2017) Mechanisms of Mixed Chimerism-Based Transplant Tolerance. Trends Immunol 38:829-843

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