Since mixed chimerism has been shown in mouse and humanized mouse models (Project 3) to have the ability not only to induce central T cell tolerance, but also to prevent new antibody responses and turn off existing antibody responses, the establishment of xenogeneic mixed chimerism remains an attractive means for achieving xenograft tolerance. Before GalT-KO miniature swine were available, the failure of attempts to achieve mixed chimerism across the pig-to-primate barrier was attributed to high levels of primate natural antibodies to the Gal antigen. However, despite the absence of the Gal antigen on the cell surface of GalT-KO hematopoeitic cells (HSC), we have found that these cells are rapidly cleared from the circulation of baboons shortly after infusion, eluding the establishment of mixed chimerism. Our data indicate that two of the most important factors playing a role in this clearance are: 1) natural antibodies to non-Gal determinants, which are variably present in different baboons;and 2) absence of the species-specific cell-membrane protein, CD47, which is required to inhibit the innate immune system from rapidly clearing cells from the circulation. The goal of this proposal is to overcome these two barriers in order to establish mixed xenogeneic chimerism of GalT-KO HSC in baboons. Specifically, we will: 1) Optimize xenogeneic bone marrow engraftment by avoiding natural and induced anti-non-Gal antibodies;2) Test effect of human CD47 on engraftment of porcine marrow in baboons using GalT-KO pig bone marrow transduced with a human CD47 expression vector;and 3) Test the effect of GalT-KO pig HSC engraftment in baboons, either alone or in combination with vascularized porcine thymus transplantation, on the induction of tolerance of GalT-KO renal xenografts.
Aim 3 will apply the findings of Aims 1 and 2, as well as strategies developed in Project 1 of this Program Project, to the mixed chimerism approach for inducing transplantation tolerance to organ xenografts in this preclinical, discordant species combination. In addition, the experiments planned will provide basic information on xenogeneic stem cell engrafment and on the immunologic pathways responsible for xenogeneic rejection and tolerance induction in primates. As such, these studies should have both theoretical and practical implications for the eventual application of xenotransplantation as a clinical modality.

Public Health Relevance

Xenotransplantation remains the best near-term hope for alleviating the critical shortage of allogeneic organs today. However, the high level of immunosuppression required to avoid rejection of xenotransplants is likely to be too dangerous for clinical use. The goal of this project is to achieve tolerance of xenotransplants through mixed chimerism, and to thereby avoid the need for immunosuppressive drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI045897-14
Application #
8688874
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
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

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