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  • Millennium Review
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Gene therapy in transplantation in the year 2000: moving towards clinical applications?

Gene Therapy volume 7, pages 14–19 (2000)Cite this article

Abstract

Transplantation faces several major obstacles that could be overcome by expression of immunomodulatory proteins through application of gene therapy techniques. Gene therapy strategies to prolong graft survival involve gene transfer of immunosuppressive or graft-protecting molecules. Very promising results have been obtained in small animal experimental models with inhibitors of co-stimulatory signals on T cells, immunosuppressive cytokines, donor major histocompatibility antigens and regulators of cell apoptosis or oxidative stress. The application of gene therapy techniques to transplantation offers a great experimental and therapeutic potential. Local production of immunosuppressive molecules may increase their therapeutic efficiency and reduce their systemic effects. When compared with other clinical situations, gene therapy in transplantation offers several potential advantages. Gene transfer into the graft can be performed ex vivo, during the transit between the donor and the recipient, thus avoiding many of the hurdles encountered with in vivo gene transfer. Furthermore, the difficulties associated with immune responses to the gene transfer vectors and transient gene expression may be easier to overcome when gene therapy protocols are applied to transplantation than when applied to other clinical situations. The next century should witness a rapid increase in the application of gene therapy techniques to large animal pre-clinical models of transplantation and later to clinical trials.

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References

  1. Cuturi MC et al. The biology of allograft rejection Curr Opin Nephrol Hypertens 1994 3: 578–584

    Article  CAS  Google Scholar 

  2. Lau H et al. Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice Science 1996 273: 109–111

    Article  CAS  Google Scholar 

  3. Madsen JC et al. Immunological unresponsiveness induced by recipient cells transfected with donor MHC genes Nature 1988 332: 161–164

    Article  CAS  Google Scholar 

  4. Sykes M et al. Specific prolongation of skin graft survival following retroviral transduction of bone marrow with an allogeneic major histocompatibility complex gene Transplantation 1993 55: 197–202

    Article  CAS  Google Scholar 

  5. Emery DW et al. Expression of an allogeneic MHC DRB transgene, through retroviral transduction of bone marrow, induces specific reduction of alloreactivity Transplantation 1997 64: 1414–1423

    Article  CAS  Google Scholar 

  6. Knechtle SJ et al. Direct MHC class I complementary DNA transfer to thymus induces donor-specific unresponsiveness, which involves multiple immunologic mechanisms J Immunol 1997 159: 152–158

    CAS  PubMed  Google Scholar 

  7. Lu L et al. Adenoviral delivery of CTLA4Ig into myeloid dendritic cells promotes their in vitro tolerogenicity and survival in allogeneic recipients Gene Therapy 1999 6: 554–563

    Article  CAS  Google Scholar 

  8. Olthoff KM et al. Adenovirus-mediated gene transfer into cold-preserved liver alografts: survival pattern and unresponsiveness following transduction with CTLA4Ig Nature Med 1998 4: 194–200

    Article  CAS  Google Scholar 

  9. Sigalla J et al. Adenovirus-mediated gene transfer into isolated adult pancreatic islets. Normal beta-cell function despite induction of an anti-adenovirus immune response Hum Gene Ther 1997 8: 1625–1634

    Article  CAS  Google Scholar 

  10. Gainer AL et al. Expression of CTLA4-Ig by biolistically transfected mouse islets promotes islet allograft survival Transplantation 1997 63: 1017–1021

    Article  CAS  Google Scholar 

  11. Qin L et al. Gene transfer of transforming growth factor-ß1 prolongs murine cardiac allograft survival by inhibiting cell-mediated immunity Hum Gene Ther 1996 7: 1981–1988

    Article  CAS  Google Scholar 

  12. Guillot C et al. Adenovirus-mediated cytokine gene transfer in heart allograft transplantation Biochem Soc Trans 1999 27: 864–869

    Article  CAS  Google Scholar 

  13. Josien R et al. A critical role for transforming growth factor-β (TGF-β) in donor transfusion-induced allograft tolerance J Clin Invest 1998 102: 1920–1926

    Article  CAS  Google Scholar 

  14. Qin L et al. Retrovirus-mediated transfer of viral IL-10 gene prolongs murine cardiac allograft survival J Immunol 1996 156: 2316–2323

    CAS  PubMed  Google Scholar 

  15. Qin L et al. Adenovirus-mediated gene transfer of viral interleukin-10 inhibits the immune response to both alloantigen and adenoviral antigen Hum Gene Ther 1997 8: 1365–1374

    Article  CAS  Google Scholar 

  16. DeBruyne LA et al. Lipid-mediated gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by inhibiting donor-specific cellular and humoral immune responses Gene Therapy 1998 5: 1079–1087

    Article  CAS  Google Scholar 

  17. Shinozaki K et al. Allograft transduction of IL-10 prolongs survival following orthothopic liver transplantation Gene Therapy 1999 6: 816–822

    Article  CAS  Google Scholar 

  18. David A et al. Prolongation of rat cardiac allograft induced by adenovirus-mediated gene transfer of IL-10 Gene Therapy (in press)

  19. Bracy JL et al. Inhibition of xenoreactive natural antibody production by retroviral gene therapy Science 1998 281: 1845–1847

    Article  CAS  Google Scholar 

  20. Kang S et al. Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction Nature Med 1997 3: 738–743

    Article  CAS  Google Scholar 

  21. Takeuchi T et al. Accelerated rejection of Fas ligand-expressing heart grafts J Immunol 1999 162: 518–522

    CAS  PubMed  Google Scholar 

  22. Swenson K et al. Fas ligand gene transfer to renal allografts in rats Transplantation 1998 65: 155–160

    Article  CAS  Google Scholar 

  23. Barkats M et al. Intrastriatal grafts of embryonic mesencephalic rat neurons genetically modified using an adenovirus encoding human Cu/Zn superoxide dismutase Neuroscience 1997 78: 703–713

    Article  CAS  Google Scholar 

  24. Zwacka RM et al. Redox gene therapy for ischemia/reperfusion injury of the liver reduces AP1 and NF-kappaB activation Nature Med 1998 4: 698–704

    Article  CAS  Google Scholar 

  25. Mignon A et al. Selective repopulation of normal mouse liver by Fas/CD95-resistant hepatocytes Nature Med 1998 4: 1185–1188

    Article  CAS  Google Scholar 

  26. Bilbao G et al. Genetic modification of liver grafts with an adenoviral vector encoding the Bcl-2 gene improves organ preservation Transplantation 1999 67: 775–783

    Article  CAS  Google Scholar 

  27. Badrichani AZ et al. Bcl-2 and Bcl-XL serve an anti-inflammatory function in endothelial cells through inhibition of NF-kappaB J Clin Invest 1999 103: 543–553

    Article  CAS  Google Scholar 

  28. Suzuki J et al. Prevention of graft coronary arteriosclerosis by antisense cdk2 kinase oligonucleotide Nature Med 1997 3: 900–903

    Article  CAS  Google Scholar 

  29. Shears LL et al. Inducible nitric oxide synthase suppresses the development of allograft arteriosclerosis J Clin Invest 1997 100: 2035–2042

    Article  CAS  Google Scholar 

  30. Cohen JL et al. Would suicide gene therapy solve the ‘T-cell dilemma’ of allogeneic bone marrow transplantation? Immunol Today 1999 20: 172–176

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Jean-Paul Soulillou and Nicolas Ferry for their critical review of the manuscript. This work was financed in part by the Association Française Contre les Myopathies (through the Gene Vector Producing Network), Association pour la Recherche sur le Cancer, the Fondation Transvie and EEC grant Biomed2 BMH4-CT98–3277.

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM) U437, and Institut de Transplantation et Recherche en Transplantation (ITERT), CHU Nantes, Cedex 01, 30 boulevard Jean Monnet, Nantes, 44093, France

    C Guillot, B Le Mauff, M C Cuturi & I Anegon

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  1. C Guillot
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  2. B Le Mauff
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  3. M C Cuturi
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  4. I Anegon
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Guillot, C., Le Mauff, B., Cuturi, M. et al. Gene therapy in transplantation in the year 2000: moving towards clinical applications?. Gene Ther 7, 14–19 (2000). https://doi.org/10.1038/sj.gt.3301083

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