iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://doi.org/10.1007/s11248-004-7268-4
Transgenic expression of CTLA4-Ig by fetal pig neurons for xenotransplantation | Transgenic Research Skip to main content

Advertisement

Springer Nature Link
Log in

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

  • Published:
Transgenic Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • AC Bachoud-Levi P Remy JP Nguyen P Brugieres JP Lefaucheur C Bourdet et al. (2000) ArticleTitleMotor and cognitive improvements in patients with Huntington’s disease after neural transplantation Lancet 356 1975–1979 Occurrence Handle10.1016/S0140-6736(00)03310-9 Occurrence Handle11130527

    Article  PubMed  Google Scholar 

  • RA Barker E Ratcliffe M McLaughlin A Richards SB Dunnett (2000) ArticleTitleA role for complement in the rejection of porcine ventral mesencephalic xenografts in a rat model of Parkinson’s disease J Neurosci 20 3415–3424 Occurrence Handle10777804

    PubMed  Google Scholar 

  • KA Berghorn JH Bonnett GE Hoffman (1994) ArticleTitlecFos immunoreactivity is enhanced with biotin amplification J Histochem Cytochem 42 1635–1642 Occurrence Handle7983364

    PubMed  Google Scholar 

  • A Bjorklund SB Dunnett P Brundin AJ Stoessl CR Freed RE Breeze et al. (2003) ArticleTitleNeural transplantation for the treatment of Parkinson’s disease Lancet Neurol 2 437–445 Occurrence Handle10.1016/S1474-4422(03)00442-3 Occurrence Handle12849125

    Article  PubMed  Google Scholar 

  • JP Bolam PN Izzo AM Graybiel (1988) ArticleTitleCellular substrate of the histochemically defined striosome/matrix system of the caudate nucleus: a combined Golgi and immunocytochemical study in cat and ferret Neuroscience 24 853–875 Occurrence Handle10.1016/0306-4522(88)90073-5 Occurrence Handle2454418

    Article  PubMed  Google Scholar 

  • T Brevig J Holgersson H Widner (2000) ArticleTitleXenotransplantation for CNS repair: immunological barriers and strategies to overcome them Trends Neurosci 23 337–344 Occurrence Handle10906793

    PubMed  Google Scholar 

  • T Brevig EB Pedersen T Kristensen J Zimmer (1997) ArticleTitleProliferative response of human T lymphocytes to porcine fetal brain cells Cell Transplant 6 571–577 Occurrence Handle10.1016/S0963-6897(97)00094-8 Occurrence Handle9440866

    Article  PubMed  Google Scholar 

  • F Cicchetti W Fodor TW Deacon C Horn Particlevan S Rollins W Burton et al. (2003) ArticleTitleImmune parameters relevant to neural xenograft survival in the primate brain Xenotransplantation 10 41–49 Occurrence Handle10.1034/j.1399-3089.2003.01130.x Occurrence Handle12535224

    Article  PubMed  Google Scholar 

  • JL Croxford JK O’Neill RR Ali K Browne AP Byrnes MJ Dallman et al. (1998) ArticleTitleLocal gene therapy with CTLA4-immunoglobulin fusion protein in experimental allergic encephalomyelitis Eur J Immunol 28 3904–3916 Occurrence Handle10.1002/(SICI)1521-4141(199812)28:12<3904::AID-IMMU3904>3.0.CO;2-5 Occurrence Handle9862327

    Article  PubMed  Google Scholar 

  • T Deacon J Schumacher J Dinsmore C Thomas P Palmer S Kott et al. (1997) ArticleTitleHistological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson’s disease Nat Med 3 350–353 Occurrence Handle10.1038/nm0397-350 Occurrence Handle9055867

    Article  PubMed  Google Scholar 

  • TW Deacon P Pakzaban LH Burns J Dinsmore O Isacson (1994) ArticleTitleCytoarchitectonic development, axon-glia relationships, and long distance axon growth of porcine striatal xenografts in rats Exp Neurol 130 151–167 Occurrence Handle10.1006/exnr.1994.1194 Occurrence Handle7821391

    Article  PubMed  Google Scholar 

  • AS Edge ME Gosse J Dinsmore (1998) ArticleTitleXenogeneic cell therapy: current progress and future developments in porcine cell transplantation Cell Transplant 7 525–539 Occurrence Handle10.1016/S0963-6897(98)00043-8 Occurrence Handle9853581

    Article  PubMed  Google Scholar 

  • B Felix ME Leger D Albe-Fessard JC Marcilloux O Rampin JP Laplace (1999) ArticleTitleStereotaxic atlas of the pig brain Brain Res Bull 49 1–137 Occurrence Handle10.1016/S0361-9230(99)00012-X Occurrence Handle10466025

    Article  PubMed  Google Scholar 

  • JS Fink JM Schumacher SL Ellias EP Palmer M Saint-Hilaire K Shannon et al. (2000) ArticleTitlePorcine xenografts in Parkinson’s disease and Huntington’s disease patients: preliminary results Cell Transplant 9 273–278 Occurrence Handle10811399

    PubMed  Google Scholar 

  • S Forss-Petter PE Danielson S Catsicas E Battenberg J Price M Nerenberg et al. (1990) ArticleTitleTransgenic mice expressing beta-galactosidase in mature neurons under neuron-specific enolase promoter control Neuron 5 187–197 Occurrence Handle10.1016/0896-6273(90)90308-3 Occurrence Handle2116814

    Article  PubMed  Google Scholar 

  • WR Galpern LH Burns TW Deacon J Dinsmore O Isacson (1996) ArticleTitleXenotransplantation of porcine fetal ventral mesencephalon in a rat model of Parkinson’s disease: functional recovery and graft morphology Exp Neurol 140 1–13 Occurrence Handle10.1006/exnr.1996.0109 Occurrence Handle8682173

    Article  PubMed  Google Scholar 

  • AR Garcia TW Deacon J Dinsmore O Isacson (1995) ArticleTitleExtensive axonal and glial fiber growth from fetal porcine cortical xenografts in the adult rat cortex Cell Transplant 4 515–527 Occurrence Handle10.1016/0963-6897(95)00027-U Occurrence Handle8520835

    Article  PubMed  Google Scholar 

  • U Grohmann C Orabona F Fallarino C Vacca F Calcinaro A Falorni et al. (2002) ArticleTitleCTLA-4-Ig regulates tryptophan catabolism in vivo Nat lmmunol 3 1097–1101 Occurrence Handle10.1038/ni846

    Article  Google Scholar 

  • M Hoehn E Kustermann J Blunk D Wiedermann T Trapp S Wecker et al. (2002) ArticleTitleMonitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat Proc Natl Acad Sci USA 99 16267–16272 Occurrence Handle10.1073/pnas.242435499 Occurrence Handle12444255

    Article  PubMed  Google Scholar 

  • M Ideguchi K Kajiwara K Yoshikawa T Uchida H Ito (2000) ArticleTitleLocal adenovirus-mediated CTLA4-immunoglobulin expression suppresses the immune responses to adenovirus vectors in the brain Neuroscience 95 217–226 Occurrence Handle10.1016/S0306-4522(99)00402-9 Occurrence Handle10619478

    Article  PubMed  Google Scholar 

  • O Isacson T Deacon (1997) ArticleTitleNeural transplantation studies reveal the brain’s capacity for continuous reconstruction Trends Neurosci 20 477–482 Occurrence Handle10.1016/S0166-2236(97)01081-3 Occurrence Handle9347616

    Article  PubMed  Google Scholar 

  • O Isacson TW Deacon P Pakzaban WR Galpern J Dinsmore LH Burn (1995) ArticleTitleTransplanted xenogeneic neural cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth patterns of glial and axonal fibres Nat Med 1 1189–1194 Occurrence Handle10.1038/nm1195-1189 Occurrence Handle7584993

    Article  PubMed  Google Scholar 

  • LC Larsson KA Czech P Brundin H Widner (2000) ArticleTitleIntrastriatal ventral mesencephalic xenografts of porcine tissue in rats: immune responses and functional effects Cell Transplant 9 261–272 Occurrence Handle10811398

    PubMed  Google Scholar 

  • O Lindvall P Brundin H Widner S Rehncrona B Gustavii R Frackowiak et al. (1990) ArticleTitleGrafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease Science 247 574–577 Occurrence Handle2105529

    PubMed  Google Scholar 

  • PS Linsley W Brady M Urnes LS Grosmaire NK Damle JA Ledbetter (1991) ArticleTitleCTLA-4 is a second receptor for the B cell activation antigen B7 J Exp Med 174 561–569 Occurrence Handle10.1084/jem.174.3.561 Occurrence Handle1714933

    Article  PubMed  Google Scholar 

  • B Melchior S Remy V Nerriere-Daguin JM Heslan JP Soulillou P Brachet (2002) ArticleTitleTemporal analysis of cytokine gene expression during infiltration of porcine neuronal grafts implanted into the rat brain J Neurosci Res 68 284–292 Occurrence Handle10.1002/jnr.10216 Occurrence Handle12111858

    Article  PubMed  Google Scholar 

  • S Ménoret M Plat G Blancho F Martinat-Botté P Bernard G Karam et al. (2004) ArticleTitleCharacterization of human CD55 and CD59 transgenic pigs and kidney xenotransplantation in the pig-to-baboon combination Transplantation 77 1468–1471 Occurrence Handle10.1097/01.TP.0000111758.35048.EA Occurrence Handle15167611

    Article  PubMed  Google Scholar 

  • V Mittoux JM Joseph F Conde S Palfi C Dautry T Poyot et al. (2000) ArticleTitleRestoration of cognitive and motor functions by ciliary neurotrophic factor in a primate model of Huntington’s disease Hum Gene Ther 11 1177–1187 Occurrence Handle10.1089/10430340050015220 Occurrence Handle10834619

    Article  PubMed  Google Scholar 

  • HT Ni RR Merica SR Spellman JM Wang WC Low (2000) ArticleTitleVisualization of antigen-specific T cell activation in vivo in response to intracerebral administration of a xenopeptide Exp Neurol 164 362–370 Occurrence Handle10.1006/exnr.2000.7435 Occurrence Handle10915575

    Article  PubMed  Google Scholar 

  • Y Okura R Tanaka K Ono S Yoshida N Tanuma Y Matsumoto (1997) ArticleTitleTreatment of rat hemiparkinson model with xenogeneic neural transplantation: tolerance induction by anti-T-cell antibodies J Neurosci Res 48 385–396 Occurrence Handle10.1002/(SICI)1097-4547(19970601)48:5<385::AID-JNR1>3.0.CO;2-A Occurrence Handle9185663

    Article  PubMed  Google Scholar 

  • FRM Pages S Klasen M Battifora D Couez R Sweet A Truneh SG Ward D Olive (1996) ArticleTitleTwo distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase association J Biol Chem 271 9403–9409 Occurrence Handle10.1074/jbc.271.16.9403 Occurrence Handle8621607

    Article  PubMed  Google Scholar 

  • P Pakzaban TW Deacon LH Burns J Dinsmore O Isacson (1995) ArticleTitleA novel mode of immunoprotection of neural xenotransplants: masking of donor major histocompatibility complex class I enhances transplant survival in the central nervous system Neuroscience 65 983–996 Occurrence Handle10.1016/0306-4522(94)00626-G Occurrence Handle7617173

    Article  PubMed  Google Scholar 

  • EB Pedersen J Zimmer B Finsen (1997) ArticleTitleTriple immunosuppression protects murine intracerebral, hippocampal xenografts in adult rat hosts: effects on cellular infiltration, major histocompatibility complex antigen induction and blood-brain barrier leakage Neuroscience 78 685–701 Occurrence Handle10.1016/S0306-4522(96)00620-3 Occurrence Handle9153651

    Article  PubMed  Google Scholar 

  • M Peschanski AC Bachoud-Levi P Hantraye (2004) ArticleTitleIntegrating fetal neural transplants into a therapeutic strategy: the example of Huntington’s disease Brain 127 1219–1228 Occurrence Handle10.1093/brain/awh145 Occurrence Handle15047588

    Article  PubMed  Google Scholar 

  • VG Pursel DJ Bolt KF Miller CA Pinkert RE Hammer RD Palmiter et al. (1990) ArticleTitleExpression and performance in transgenic pigs J Reprod Fertil Suppl 40 235–245 Occurrence Handle2192041

    PubMed  Google Scholar 

  • S Remy C Canova V Daguin-Nerriere C Martin B Melchior I Neveu et al. (2001) ArticleTitleDifferent mechanisms mediate the rejection of porcine neurons and endothelial cells transplanted into the rat brain Xenotransplantation 8 136–148 Occurrence Handle10.1034/j.1399-3089.2001.00076.x Occurrence Handle11328584

    Article  PubMed  Google Scholar 

  • S Sergent-Tanguy C Chagneau I Neveu P Naveilhan (2003) ArticleTitleFluorescent activated cell sorting (FACS): a rapid and reliable method to estimate the number of neurons in a mixed population J Neurosci Methods 129 73–79 Occurrence Handle10.1016/S0165-0270(03)00210-3 Occurrence Handle12951234

    Article  PubMed  Google Scholar 

  • A Tsuji I Tamai A Sakata Y Tenda T Terasaki (1993) ArticleTitleRestricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, P-glycoprotein Biochem Pharmacol 46 1096–1099 Occurrence Handle10.1016/0006-2952(93)90677-O Occurrence Handle8105783

    Article  PubMed  Google Scholar 

  • RM Twyman EA Jones (1997) ArticleTitleSequences in the proximal 5′ flanking region of the rat neuron-specific enolase (NSE) gene are sufficient for cell type-specific reporter gene expression J Mol Neurosci 8 63–73 Occurrence Handle9061616

    PubMed  Google Scholar 

  • T Uchida K Kajiwara M Ideguchi K Yoshikawa J Morioka M Suzuki (2001) ArticleTitleCo-administration of adenovirus vector expressing CTLA4-Ig prolongs transgene expression in the brain of mice sensitized with adenovirus Brain Res 898 272–280 Occurrence Handle10.1016/S0006-8993(01)02194-1 Occurrence Handle11306013

    Article  PubMed  Google Scholar 

  • PM Wallace JS Johnson JF MacMaster KA Kennedy P Gladstone PS Linsley (1994) ArticleTitleCTLA4Ig treatment ameliorates the lethality of murine graft-versus-host disease across major histocompatibility complex barriers Transplantation 58 602–610 Occurrence Handle8091487

    PubMed  Google Scholar 

  • PM Wallace JN Rodgers GM Leytze JS Johnson PS Linsley (1995) ArticleTitleInduction and reversal of long-lived specific unresponsiveness to a T-dependent antigen following CTLA4Ig treatment J Immunol 154 5885–5895 Occurrence Handle7751633

    PubMed  Google Scholar 

  • H Wenkel JW Streilein MJ Young (2000) ArticleTitleSystemic immune deviation in the brain that does not depend on the integrity of the blood-brain barrier J Immunol l 64 5125–5131

    Google Scholar 

  • MJ Wood DJ Sloan KJ Wood HM Charlton (1996) ArticleTitleIndefinite survival of neural xenografts induced with anti-CD4 monoclonal antibodies Neuroscience 70 775–789 Occurrence Handle10.1016/S0306-4522(96)83014-4 Occurrence Handle9045088

    Article  PubMed  Google Scholar 

Download references

Author information

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
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martine Plat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Véronique Nerrière-Daguin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Flora Coulon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Svetlana Uzbekova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric Venturi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Françoise Condé
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-Michel Hermel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Philippe Hantraye
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Laurent Tesson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ignacio Anegon
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Benoit Melchior
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marc Peschanski
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Brigitte Le Mauff
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Françoise Boeffard
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Solène Sergent-Tanguy
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Isabelle Neveu
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Philippe Naveilhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Jean-Paul Soulillou
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Michel Terqui
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Philippe Brachet
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Bernard Vanhove
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernard Vanhove.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

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

Keywords

Search

Navigation