title: Transgenic expression of human CD47 markedly increases engraftment in a murine model of pig-to-human hematopoietic cell transplantation.
abstract: Mixed chimerism approaches for induction of tolerance of solid organ transplants have been applied successfully in animal models and in the clinic. However, in xenogeneic models (pig-to-primate), host macrophages participate in the rapid clearance of porcine hematopoietic progenitor cells, hindering the ability to achieve mixed chimerism. CD47 is a cell-surface molecule that interacts in a species-specific manner with SIRPα receptors on macrophages to inhibit phagocytosis and expression of human CD47 (hCD47) on porcine cells has been shown to inhibit phagocytosis by primate macrophages. We report here the generation of hCD47 transgenic GalT-KO miniature swine that express hCD47 in all blood cell lineages. The effect of hCD47 expression on xenogeneic hematopoietic engraftment was tested in an in vivo mouse model of human hematopoietic cell engraftment. High-level porcine chimerism was observed in the bone marrow of hCD47 progenitor cell recipients and smaller but readily measurable chimerism levels were observed in the peripheral blood of these recipients. In contrast, transplantation of WT progenitor cells resulted in little or no bone marrow engraftment and no detectable peripheral chimerism. These results demonstrate a substantial protective effect of hCD47 expression on engraftment and persistence of porcine cells in this model, presumably by modulation of macrophage phagocytosis.
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA.
authors.forename: A
authors.initials: A
authors.lastname: Tena
authors.forename: J
authors.initials: J
authors.lastname: Kurtz
authors.forename: D A
authors.initials: DA
authors.lastname: Leonard
authors.forename: J R
authors.initials: JR
authors.lastname: Dobrinsky
authors.forename: S L
authors.initials: SL
authors.lastname: Terlouw
authors.forename: N
authors.initials: N
authors.lastname: Mtango
authors.forename: J
authors.initials: J
authors.lastname: Verstegen
authors.forename: S
authors.initials: S
authors.lastname: Germana
authors.forename: C
authors.initials: C
authors.lastname: Mallard
authors.forename: J S
authors.initials: JS
authors.lastname: Arn
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.forename: R J
authors.initials: RJ
authors.lastname: Hawley
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001853:Bone Marrow / Q000276:immunology*; D051928:CD47 Antigen / Q000276:immunology* / Q000378:metabolism; D046528:Chimerism; D005700:Galactosyltransferases / Q000235:genetics; D055786:Gene Knockout Techniques; D006085:Graft Survival / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010587:Phagocytosis / Q000502:physiology; D013552:Swine; D013556:Swine, Miniature; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning; D014183:Transplantation, Heterologous
chemical_list: D051928:CD47 Antigen; C497894:CD47 protein, human; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase
keywords: Animal models: nonhuman primate; animal models: porcine; basic (laboratory) research/science; immunosuppression/immune modulation; tolerance: chimerism; xenotransplantation