Mixed xenogeneic chimerism is a promising approach to achieving tolerance across species barriers. This approach is being explored in nonhuman primates in Project 2. The studies in Project 3 will complement those in the nonhuman primate model by exploring the ability of porcine mixed xenogeneic chimerism to tolerize non-T cell components of the human immune system and analyzing the function of xenotolerant human T cells in detail. We have developed a humanized mouse model that allows generation of functional human T cells and B cells as well as human dendritic cells of several classes. These mice mount effective T cell responses and class-switched IgG responses following immunization and produce natural anti-pig xenoantibodies. We have also generated transgenic immunodeficient mice expressing porcine cytokines that promote porcine hematopoiesis from pig bone manow cells (BMCs). Using this model, we have demonstrated that the addition of porcine BMCs to the humanized mouse model results in central T cell tolerance induction specifically to the pig BMC donor, with preserved responsiveness to allogeneic and third party pig antigens. Our previous studies in the rat to mouse species combination have demonstrated that even low levels of mixed xenogeneic chimerism tolerize T cells centrally and tolerize natural killer (NK) cells and pre-existing natural antibody-producing B cells to the xenogeneic donor. In this proposal we will use this humanized mouse model to explore the ability of mixed porcine chimerism to tolerize human NK cells and B cells. We will also assess T cell function and the ability to clear opportunistic infections in pig-human mixed xenogeneic chimeras. We will: 1) Explore the ability of mixed xenogeneic chimerism to induce human NK cell tolerance in the pig-human species combination;2) Explore the ability of mixed xenogeneic chimerism to induce human natural antibody-producing B cell tolerance in the pig-human species combination;and 3) Compare T cell immune responses in humanized mice with and without porcine mixed xenogeneic chimerism. These studies will assess T cell immune recognition in further detail and determine the ability to tolerize additional components of the human immune system that pose significant barriers to xenotransplantation. They have direct bearing on the mixed chimerism strategy being explored in the pig-->baboon model in Project 2 and will determine the potential utility of adding BMT to thymic transplantation in Project 1. The studies are also highly relevant to the non-Gal Nab studies in Projects 1 and 4.

Public Health Relevance

The severe shortage of allogeneic donors currently limits the number of transplants performed. This supply-demand disparity could be corrected by the ability to use organs from other species (xenografts), but the immune barriers to xenografts make it unlikely that non-specific immunosuppression could prevent rejection without unacceptable toxicity. We have developed an approach to achieving xenograft tolerance among human T cells, thereby avoiding the need for non-specific immunosuppression and we now propose studies that will advance this promising approach toward clinical application.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI045897-13
Application #
8499191
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
13
Fiscal Year
2013
Total Cost
$411,222
Indirect Cost
$121,193
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Takenaka, Maisa C; Robson, Simon; Quintana, Francisco J (2016) Regulation of the T Cell Response by CD39. Trends Immunol 37:427-39
Am Esch, Jan Schulte; Schmelzle, Moritz; Duhme, Constanze et al. (2016) Reply to Letter: "Infusion of CD133+ Bone Marrow-Derived Stem Cell After Selective Portal Vein Embolization Enhances Functional Hepatic Reserves After Extended Right Hepatectomy". Ann Surg 263:e44-5
Hu, Zheng; Xia, Jinxing; Fan, Wei et al. (2016) Human melanoma immunotherapy using tumor antigen-specific T cells generated in humanized mice. Oncotarget 7:6448-59
Lazar, Zsofia; Müllner, Nina; Lucattelli, Monica et al. (2016) NTPDase1/CD39 and aberrant purinergic signalling in the pathogenesis of COPD. Eur Respir J 47:254-63
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

Showing the most recent 10 out of 163 publications