title: Transgenic expression of CTLA4-Ig by fetal pig neurons for xenotransplantation.
abstract: The transplantation of fetal porcine neurons is a potential therapeutic strategy for the treatment of human neurodegenerative disorders. A major obstacle to xenotransplantation, however, is the immune-mediated rejection that is resistant to conventional immunosuppression. To determine whether genetically modified donor pig neurons could be used to deliver immunosuppressive proteins locally in the brain, transgenic pigs were developed that express the human T cell inhibitory molecule hCTLA4-Ig under the control of the neuron-specific enolase promoter. Expression was found in various areas of the brain of transgenic pigs, including the mesencephalon, hippocampus and cortex. Neurons from 28-day old embryos secreted hCTLA4-Ig in vitro and this resulted in a 50% reduction of the proliferative response of human T lymphocytes in xenogenic proliferation assays. Transgenic embryonic neurons also secreted hCTLA4-Ig and had developed normally in vivo several weeks after transplantation into the striatum of immunosuppressed rats that were used here to study the engraftment in the absence of immunity. In conclusion, these data show that neurons from our transgenic pigs express hCTLA4-Ig in situ and support the use of this material in future pre-clinical trials in neuron xenotransplantation.
authors.affiliation: Institut de Transplantation et de Recherche en Transplantation, INSERM U643, CHU Hôtel Dieu, 30, Bld J Monnet, Nantes, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Martin
authors.forename: Martine
authors.initials: M
authors.lastname: Plat
authors.forename: Véronique
authors.initials: V
authors.lastname: Nerriére-Daguin
authors.forename: Flora
authors.initials: F
authors.lastname: Coulon
authors.forename: Svetlana
authors.initials: S
authors.lastname: Uzbekova
authors.forename: Eric
authors.initials: E
authors.lastname: Venturi
authors.forename: Françoise
authors.initials: F
authors.lastname: Condé
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Hermel
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.forename: Laurent
authors.initials: L
authors.lastname: Tesson
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
authors.forename: Benoit
authors.initials: B
authors.lastname: Melchior
authors.forename: Marc
authors.initials: M
authors.lastname: Peschanski
authors.forename: Brigitte
authors.initials: B
authors.lastname: Le Mauff
authors.forename: Françoise
authors.initials: F
authors.lastname: Boeffard
authors.forename: Solène
authors.initials: S
authors.lastname: Sergent-Tanguy
authors.forename: Isabelle
authors.initials: I
authors.lastname: Neveu
authors.forename: Philippe
authors.initials: P
authors.lastname: Naveilhan
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.forename: Michel
authors.initials: M
authors.lastname: Terqui
authors.forename: Philippe
authors.initials: P
authors.lastname: Brachet
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
mesh_terms: D000069594:Abatacept; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D016332:Fetal Tissue Transplantation / Q000276:immunology*; D005434:Flow Cytometry; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy / Q000379:methods; D009474:Neurons / Q000276:immunology* / Q000637:transplantation; D051381:Rats / Q000235:genetics; D013552:Swine / Q000235:genetics; D013601:T-Lymphocytes; D019076:Transgenes; D014181:Transplantation Immunology; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D018796:Immunoconjugates; D000069594:Abatacept