title: Regulation of macrophage-mediated xenocytotoxicity by overexpression of alpha-2,6-sialyltransferase in swine endothelial cells.
abstract: Macrophages play an important role in xenogenic rejection and therefore may represent a major obstacle in clinical application of xenograft. CD33-related sialic acid-binding immunoglobulin-like lectins (Siglecs) belong to the immunoglobulin superfamily and contain a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) that is able to inhibit cytokine production. Because human macrophages express various CD33-related Siglecs, we hypothesized that overexpression of α-2,6-sialyltransferase (2,6-ST) in swine endothelial cells (SECs) might prevent the cytotoxicity mediated by macrophages. To confirm our hypothesis, the cytotoxicity of macrophages against 2,6-ST-overexpressing SECs was determined with the use of in vitro-generated macrophages as an effector and naïve or 2,6-ST-overexpressing SECs as a target. The 2,6-ST-overexpressing SECs were established by transfection with the genes for 2,6-ST. Transfection of 2,6-ST led to significant reduction in cytotoxicity compared with naïve SECs. These findings indicate that the sialylated ligands against CD33-related Siglecs may provide an effective therapeutic strategy to inhibit macrophage-mediated xenograft rejection in xenotransplantation.
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address: amaeda@orgtrp.med.osaka-u.ac.jp.
authors.forename: A
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakahata
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Usui
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyagawa
mesh_terms: D000818:Animals; D002460:Cell Line; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000201:enzymology / Q000276:immunology*; D004790:Enzyme Induction; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D008024:Ligands; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000276:immunology / Q000378:metabolism; D012799:Sialyltransferases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D013552:Swine; D014162:Transfection; D014183:Transplantation, Heterologous; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D008024:Ligands; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D012799:Sialyltransferases; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase