Xenotransplantation from pigs has the potential to resolve the growing shortage of human organ donors. Because of the extensive molecular incompatibilities between the donor and host, innate immunity plays a much greater role in xenograft rejection than in allograft rejection. CD47 is ubiquitously expressed and serves as a ligand of SIRP?, an inhibitory receptor on macrophages and DCs. During the current funding period, we demonstrated that the lack of cross-species interaction in CD47-SIRP? pathway largely accounts for macrophage-mediated rejection of hematopoietic and non-hematopoietic cellular xenografts. Transplantation of CD47-deficient cells induces rapid innate immune activation in syngeneic wild-type (WT) mice. Furthermore, CD47-SIRP? signal is required to repress recipient CD11hiCD8?- DC activation and induce tolerance after donor-specific transfusion (DST). Based on these and other data presented in the application, we hypothesize that the interaction between donor CD47 and host SIRP? is essential for controlling activation of SIRP?+ macrophages and DCs, and that the absence of this interaction activates host macrophages and DCs, hence stimulating anti-donor T cell responses. Here, we propose 3 specific aims to test our hypothesis.
Aim 1 is to elucidate the role of CD47-SIPR? signaling in the regulation of SIRP?+ innate immune cell activation after hepatocyte xenotransplantation. We will transplant CD47 KO mouse hepatocytes into syngeneic WT mice to analyze innate immune cell activation and graft rejection induced solely by CD47 disparity. We will also transplant human CD47 transgenic vs. control pig hepatocytes into humanized mice to determine whether human CD47 expression may inhibit human innate immune responses to pig xenografts.
Aim 2 is to determine the role of "missing CD47"-induced innate immune cell activation in T cell xenoresponses after hepatocyte transplantation. We will first address this question in allotransplant models, in which CD47 KO mice will be used to mimic CD47-incompatible xenogeneic donors. We will examine anti-donor T cell responses by in vitro and adoptive T cell transfer assays. We will then investigate the potential of human CD47 expression on pig hepatocytes to attenuate human T cell xenoimmune responses using humanized mice with a functional human immune system.
Aim 3 is to determine the mechanisms by which CD47 on donor cells facilitates tolerance induction in DST plus costimulatory blockade-treated recipients. We will identify the DC and macrophage populations that are rapidly activated after CD47-deficient DST and their roles in T cell activation and tolerance induction. We will address these questions in a mouse model of CD47-deficient cardiac allotransplantation, and a pig-to-mouse xenotransplantation model that involves DST from human CD47-transgenic pigs into humanized mice. These studies are expected to provide significant insights into the mechanisms by which CD47 incompatibility activates innate and adaptive xenoimmune responses, and the potential of using human CD47 transgenic pigs as donors to facilitate xenotolerance induction and xenograft survival.

Public Health Relevance

The robust immunological rejection poses a major obstacle to clinical xenotransplantation, a possible solution to the severe worldwide shortage of human organ donors. This proposal aims to further understand the mechanisms of xenoimmune responses and to develop strategies for improving xenograft survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064569-08
Application #
8622183
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Nabavi, Nasrin N
Project Start
2005-04-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
8
Fiscal Year
2014
Total Cost
$328,087
Indirect Cost
$106,853
Name
Columbia University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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
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
Rong, Zhili; Wang, Meiyan; Hu, Zheng et al. (2014) An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell 14:121-30
Wang, Hui; Yang, Yong-Guang (2014) The complex and central role of interferon-? in graft-versus-host disease and graft-versus-tumor activity. Immunol Rev 258:30-44
Wang, Yi; Wang, Hui; Xia, Jinxing et al. (2013) Activated CD8 T cells acquire NK1.1 expression and preferentially locate in the liver in mice after allogeneic hematopoietic cell transplantation. Immunol Lett 150:75-8
Hu, Zheng; Yang, Yong-Guang (2012) Human lymphohematopoietic reconstitution and immune function in immunodeficient mice receiving cotransplantation of human thymic tissue and CD34(+) cells. Cell Mol Immunol 9:232-6
Wang, Hui; Yang, Yong-Guang (2012) Innate cellular immunity and xenotransplantation. Curr Opin Organ Transplant 17:162-7
Hu, Zheng; Van Rooijen, Nico; Yang, Yong-Guang (2011) Macrophages prevent human red blood cell reconstitution in immunodeficient mice. Blood 118:5938-46
Navarro-Alvarez, Nalu; Yang, Yong-Guang (2011) CD47: a new player in phagocytosis and xenograft rejection. Cell Mol Immunol 8:285-8

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