Regulation of innate and adaptive immune responses in xenotransplantation by modulating CD47sirp α signaling
| Project/Area Number |
18390348
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Hiroshima University |
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Principal Investigator |
OHDAN Hideki Hiroshima University, Graduate School of Biomedical Sciences, Associate Professor (10363061)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIYAMA Kohei Hiroshima University, Hospital, Assistant Professor (50437589)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,130,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2007: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2006: ¥7,900,000 (Direct Cost: ¥7,900,000)
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| Keywords | xenotransplantation / macrophage / T cell immune response / self-recognition system |
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| Research Abstract |
It has been reported that macrophage-induced cytotoxicity is involved in lon-term xenograft survival, however, the mechanism has remained unknown. A recent report indicates that the signal regulatory protein (SIRP) α is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRPα, prevents autologous phagocytosis. We confirmed that interspecies incompatibility of CD47 significantly contributes to the rejection of xenogeneic cells by macrophages. Genetic induction of human CD47 on porcine cells could provide inhibitory signaling to SIRPα on human macrophages, providing a novel approach to preventing macrophage-mediated xenograft rejection. CD47-SIRPα signaling system may also play an important role in adaptive immune response. We have analyzed the frequency and proliferative activity of human T cells responding to either porcine or allogenic PBMCs by using in vitro mixed lymphocyte reaction (MLR) assay with a CFSE-labeling technique. The freque
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ncies of alloreactive and xenoreactive CD4^+ T cell precursors were almost identical, however, the Stimulation Index (SI) of xenoreactive CD4^+ T cells was significantly higher than that of alloreactive, indicating a stronger reaction by a single xenoreactive CD4^+ T cell. Moreover, when CD4^+ T cells were depleted from the responders in the MLR, the proliferation of xenoreactive CD8^+ T cells was significantly less than that of alloreactive CD8^+ T cells, indicating that the human CD4^+ T cells, but not CDS, T cells, are sufficient to induce porcine xenograft rejection. Further, The SI of xenoreactive CDC and Cost T cells was also significantly suppressed in the presence of human CD47-Fc. These results suggest that the human T cell responses to porcine cells are stronger than those to allogeneic cells because of the interspecies incompatibility of CD47. Moreover, genetic manipulation of porcine cells to induce human CD47 expression might attenuate human T cell-mediated xenograft rejection. Less
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Report
(3 results)
Research Products
(49 results)
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[Journal Article] Role for CD47-SIRPalpha signaling in xenograft injection by macrophages2007
Author(s)
K., Ide, H., Wang, H., Tahara,J., Liu, X., Wang, T., Asahara, M., Sykes, Y.G., Yang, H., Ohdan
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Journal Title
PNAS 20, 104(12)
Pages: 5062-6
Description
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[Journal Article] Alphal,3-galactosyltransferase gene-knockout pigs for xenotransplantation : where do we go from here2007
Author(s)
D.K., Cooper, A., Dorling, R.N., Pierson, 3rd, M., Rees, J., Seebach, M., Yazer, H.,Ohdan, M., Awwad, D., Ayares
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Journal Title
Transplantation 15, 84(1)
Pages: 1-7
Description
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[Journal Article] Evidence of immune tolerance to blood group antigens in a case of ADO-incompatible pediatric liver transplantation2007
Author(s)
H., Ohdan, W., Zhou, Y., Tanaka, T., Irei, Y., Fuchimoto, H., Egawa, T., Asahara
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Journal Title
An J Transplant 7(9)
Pages: 2190-4
Description
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[Journal Article] Tho persistent elimination of B cells responding to blood group A carbohydrates by synthetic group A carbohydrates and B-1 cell differentiation blockade : novel concept in preventing antibody-mediated rejection in ABO-incompatible transplantation2007
Author(s)
H.,Ohdan, W., Zhou, K., Ishiyama, Y., Tanaka, K., Idc, T., Asahara
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Journal Title
Blood 15, 110(13)
Pages: 4567-75
Description
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[Journal Article] Characterization of anti-Gal antibody-producing cells of baboons and humans2006
Author(s)
Y.,Xu, Y.,C.,Yang, H.,Ohdan, D.Ryan,D.,Harper, C.Wu, H.S.,Kruge-Grey, A.D.Thall, M., Awwad, M., Sykes
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Journal Title
Transplantation 27, 81(6)
Pages: 940-8
Description
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[Journal Article] Liver sinusoidal endothelial cells that endocytose allogeneic cells suppress T cells with indirect allospecificity2006
Author(s)
D.,Tokita, M.,Shishida, H.,Ohdan, T.,Onoe, H.,Hara, Y.,Tanaka, K.,Ishiyama, H.,Mitsuta, K.,Ide, K.,Arihiro, T.,Asahara
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Journal Title
J Immunol 15, 177(6)
Pages: 3615-24
Description
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[Presentation] Rejection and Cytotoxicity against xenogeneic antigen N-glycolylneuraminic acid (NeuGc)2008
Author(s)
H., Tahara, H., Ohdan, K., Ide, N., Basnet, K.,Ishiyama, M., Shishida, Y., Tanaka, T., Irei, M., Ohira, Y., Igarashi, K., Kajitani, M., Banshodani, H., Takematsu, Y., Kozutsumi, T., Asahara
Organizer
The 11th meeting of Japanese Xenotransplantaion Society
Place of Presentation
Osaka
Year and Date
2008-02-23
Description
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[Presentation] Comparative detection of natural antibodies to a-Gal and NeuGc epitopes in human sera2008
Author(s)
N., Basnet, H., Ohdan, H., Tahara, K., Ide, K., Ishiyama, M., Shishida, Y., Tanaka, T., Irei, M., Ohira, Y., Igarashi, K., Kajitani, M., Banshodani, H., Takematsu, Y., Kozutsumi, T., Asahara
Organizer
The 11th meeting of Japanese Xenotransplantaion Society
Place of Presentation
Osaka
Year and Date
2008-02-23
Description
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[Presentation] Antibody-dependent rejection against xenogeneic antigen N-glycolylneuraminic acid (NeuGc)2007
Author(s)
H., Tahara, H., Ohdan, K., Ide, N., Basnet, K., Ishiyama, M., Shishida, Y., Tanaka, T., Irei, M., Ohira, Y., Igarashi, K., Kajitani, M., Banshodani, H., Takematsu, Y., Kozutsumi, T., Asahara
Organizer
The 43th annual meeting of Japan Society for Transplantation
Place of Presentation
Sendai
Year and Date
2007-11-24
Description
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[Presentation] Role of antibodies against N-glycolylneuraminic acid (NeuGc) in acute vascular rejection caused by anti-non-Gal antibodies2007
Author(s)
H., Tahara, H., Ohdan, K., Ide, N., Basnet, H., Takamatsu, Y., Kozutsumi, T., Asahara
Organizer
CTS-IPITA-IXA 2007 Joint Conference
Place of Presentation
Mineapolis, USA
Year and Date
2007-09-19
Description
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[Presentation] Genetic induction of human CD47 on porcine cells prevents Macrophagemediated xenograft rejection through inhibitory signaling to SIRPα2007
Author(s)
K., Ide, H., Wang, H., Tahara, T., Asahara, M., Sykes, Y.G., Yang, H., Ohdan
Organizer
CTS-IPITA-IXA 2007 Joint Conference
Place of Presentation
Mineapolis, USA
Year and Date
2007-09-17
Description
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[Presentation] Immunogenicity of N-glycolylneuraminic acid (NeuGc) in Xenotransplantation2007
Author(s)
H., Tahara, H., Ohdan, K., Ide, N., Basnet, H., Takamatsu, Y., Kozutsumi, T., Asahara
Organizer
American Transplant Congress 2007
Place of Presentation
San Francisco, USA
Year and Date
2007-05-07
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Immunogenicity of xenogeneic antigen N-glycolylneuraminic acid (NeuGc)2007
Author(s)
H., Tahara, H., Ohdan, K., Ide, N., Basnet, K., Ishiyama, M., Shishida, Y., Tanaka, T., Irei, M., Ohira, Y., Igarashi, H., Takematsu, Y., Kozutsumi, T., Asahara
Organizer
The 107th annual congress of Japan Surgical Society
Place of Presentation
Osaka
Year and Date
2007-04-12
Description
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[Presentation] Mechanism of avoidance of xenogeneic rejection by macrophages through intracellular inhibitory CD47-SHIPα signaling2007
Author(s)
K., Ide, H., Ohdan, H., Tahara, N., Basnet, K.,Ishiyama, Y., Tanaka, M., Shishida, T., Irei, M., Ohira, Y., Igarashi, T., Asahara
Organizer
The 10th meeting of Japanese Xenotransplantaion Society
Place of Presentation
Tokyo
Year and Date
2007-03-10
Description
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[Presentation] Immunogenicity of xenogeneic antigen N-glycolylneuraminic acid (NeuGc)2007
Author(s)
H., Tahara, H., Ohdan, K., Ide, N., Basnet, K., Ishiyama, M., Shishida, Y., Tanaka, T., Irei, M., Ohira, Y., Igarashi, M., Doskali, H., Takematsu, Y., Kozutsumi, T., Asahara
Organizer
The 10th meeting of Japanese Xenotransplantaion Society
Place of Presentation
Tokyo
Year and Date
2007-03-10
Description
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[Presentation] Avoidance of xenogeneic rejection by macrophages through intracellular inhibitory CD47-SIRPα signaling2006
Author(s)
K., Ide, H., Ohdan, H., Tahara, K., Ishiyama, Y., Tanaka, M., Shishida, T., Irei, M., Ohira, T., Asahara
Organizer
The 42th annual meeting of Japan Society for Transplantation
Place of Presentation
Chiba
Year and Date
2006-09-08
Description
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[Presentation] Human CD47 expression protects porcine cells from xenogeneic human macrophage phagocyrtosis through inhibitory CD47-S1RPα signaling2006
Author(s)
K., Ide, H., Wang, T., Asahara, M., Sykes, Y.G., Yang, H., Ohdan
Organizer
The First Joint International Transplant Meeting /The Transplantation Society (TTS)-WTC2006
Place of Presentation
Boston, USA
Year and Date
2006-07-23
Description
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