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Transgenic expression of CTLA4-Ig by fetal pig neurons for xenotransplantation

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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.

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Authors and Affiliations

  1. Institut de Transplantation et de Recherche en Transplantation, INSERM U643, CHU Hôtel Dieu, 30, Bld J, Monnet, Nantes, France

    Caroline Martin, Flora Coulon, Laurent Tesson, Ignacio Anegon, Benoit Melchior, Brigitte Le Mauff, Françoise Boeffard, Solène Sergent-Tanguy, Isabelle Neveu, Philippe Naveilhan, Jean-Paul Soulillou, Philippe Brachet & Bernard Vanhove

  2. INRA Physio Repro Reproduction Femelle CR de Tours, 37380, Nouzilly, France

    Martine Plat, Véronique Nerrière-Daguin, Svetlana Uzbekova, Eric Venturi & Michel Terqui

  3. Service Hospitalier Frédéric Joliot, URA CEA CNRS 2210, 4 place du Général Leclerc, 91401, Orsay, France

    Françoise Condé, Jean-Michel Hermel & Philippe Hantraye

  4. Faculté de Médecine, INSERM U421 8 rue du Général Sarrail, 94010, Créteil, France

    Marc Peschanski

Authors
  1. Caroline Martin
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  2. Martine Plat
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  3. Véronique Nerrière-Daguin
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  4. Flora Coulon
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  5. Svetlana Uzbekova
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  6. Eric Venturi
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  7. Françoise Condé
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  8. Jean-Michel Hermel
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  10. Laurent Tesson
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  11. Ignacio Anegon
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  12. Benoit Melchior
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  16. Solène Sergent-Tanguy
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  17. Isabelle Neveu
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  18. Philippe Naveilhan
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  19. Jean-Paul Soulillou
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  20. Michel Terqui
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  21. Philippe Brachet
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  22. Bernard Vanhove
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Correspondence to Bernard Vanhove.

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Martin, C., Plat, M., Nerrière-Daguin, V. et al. Transgenic expression of CTLA4-Ig by fetal pig neurons for xenotransplantation. Transgenic Res 14, 373–384 (2005). https://doi.org/10.1007/s11248-004-7268-4

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  • DOI: https://doi.org/10.1007/s11248-004-7268-4

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