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Adenovirus-mediated gene transfer into cold-preserved liver allografts: Survival pattern and unresponsiveness following transduction with CTLA4Ig

A Correction to this article was published on 01 March 1998

Abstract

The immune response of liver transplant recipients was modulated via adenovirus-mediated transduction of the cold-preserved liver with sequences encoding CTLA4lg. Transplanted allografts demonstrated rapid transient local expression and recombinant protein production shortly after revascularization, resulting in intact liver function, indefinite survival of the recipient, and the development of donor-specific unresponsiveness. Lymphocytic infiltration of the graft was mainly of the T helper 2 (Th2) subset and was not associated with injury to primary cellular targets of the alloimmune response. These findings demonstrate a successful outcome of a feasible and potentially clinically relevant system of gene delivery of sequences encoding proteins capable of inhibiting the alloimmune response.

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References

  1. Grusby, M.J. et al. Mice lacking major histocompatibility complex class I and class II molecules. Proc Natl. Acad. Sci. USA 90, 3913–3917 (1993).

    Article  CAS  Google Scholar 

  2. Auchincloss, J. Jr., et al. The role of “indirect” recognition in initiating rejection of skin grafts from major histocompatibility complex class II-deficient mice. Proc. Natl. Acad. Sci. USA 90, 3373–3377 (1993).

    Article  CAS  Google Scholar 

  3. Cozzi, D. & White, D.J. The generation of transgenic pigs as potential organ donors for humans. Nature Med. 1, 964–966 (1995).

    Article  CAS  Google Scholar 

  4. Byrne, G.W. et al. Transgenic pigs expressing human CD59 and decay-accelerating factor produce an intrinsic barrier to complement-mediated damage. Transplantation 63,149–155 (1997).

    Article  CAS  Google Scholar 

  5. Snaked, A. et al. Adenovirus-mediated gene transfer in the transplant setting II: Successful expression of transferred cDNA in syngeneic liver grafts. Transplantation 57, 1508–1511 (1994).

    Article  Google Scholar 

  6. Drazan, K.E., et al. In vivo adenoviral-mediated human p53 tumor suppressor gene transfer and expression in rat liver after resection. Surgery 116, 197–204 (1994).

    Google Scholar 

  7. Drazan, K.E., Chen, X.D., Busuttil, R.W., Csete, M. & Shaked, A. Gene transfer in the transplant setting III: Variables affecting recombinant gene expression in liver grafts. Transplantation 59, 670–673 (1995).

    Article  CAS  Google Scholar 

  8. Drazan, K.E. et al. Hepatic liver function is preserved after adenoviral-mediated gene transfer. J.Surg.Res. 59, 299–304 (1995).

    Article  CAS  Google Scholar 

  9. Lin, H. et al. Long-term acceptance of major histocompatibility complex mismatched cardiac allograft induced by CTLA4lg plus donor-specific transfusion. J. Exp. Med. 178, 1801–1806 (1993).

    Article  Google Scholar 

  10. Baliga, P. et al. CTLA4lg prolongs allograft survival while suppressing cell-mediated immunity. Transplantation 58, 1082–1090 (1994).

    Article  Google Scholar 

  11. Lenschow, D.J. et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig. Science 257, 789–792 (1992).

    Article  Google Scholar 

  12. Wang, J. jiano, S., Wolff, J.A., & Knechtle, S.J. Gene transfer and expression in rat cardiac transplant. Transplantation 53, 703–705 (1992).

    Article  CAS  Google Scholar 

  13. Shaked, A. et al. Retroviral-mediated gene transfer into rat experimental liver transplant. Transplantation 57, 32–32 (1994).

    Article  CAS  Google Scholar 

  14. Csete, M.E. et al. Adenovirus-mediated gene transfer in the transplant setting. I. Conditions for expression of transferred gene in cold preserved hepatocytes. Transplantation 57, 1502–1507 (1994).

    Article  Google Scholar 

  15. Tripathy, S.K., Black, H.B., Goldwasser, E. & Leiden, J.M. Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nature Med. 2, 545–550 (1996).

    Article  CAS  Google Scholar 

  16. Yang, Y., Su, Q. & Wilson, J.M. Role of viral antigens in destructive cellular immune responses to adenovirus vector-transduced cells in mouse lungs. J. Virol. 70, 7209–7212(1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yang, Y., Jooss, K.U., Su, Q., Ertl, H.C. & Wilson, J.M. Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo. Gene Ther. 3,137–144 (1996).

    PubMed  Google Scholar 

  18. Linsley, P.S. et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 257, 792–795 (1992).

    Article  Google Scholar 

  19. Sayegh, M.H., et al. CD28-B7 blockade after alloantigenic challenge in vivo inhibits Thi cytokines but spares Th2. J. Exp. Med. 181, 1869–1874 (1995).

    Google Scholar 

  20. Judge, T.A., et al. The in vivo mechanisms of action of CTLA4Ig. J. Immunol. 156, 2294–2299 (1996).

    Google Scholar 

  21. Kamada, N. & Calne, R.Y. Orthotopic liver transplantation in the rat: Technique using cuff for portal vein anastomosis and biliary drainage. Transplantation 28, 47 (1979).

    Article  CAS  Google Scholar 

  22. Lin, H., lammattoni, M.D., Modblum, J.R., & Boiling, S.F. Experimental hetero-topic heart transplantation without ischemia or reperfusion. J. Heart Transplant.9,720(1990).

  23. Hirt, J.M.B. Selective extraction of polyoma DNA from infected mouse cell cultures. J. Mol. Biol. 26, 365–369 (1967).

    Article  Google Scholar 

  24. Graham, F.L. & van der Eb A.J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 52 2(2)456–467 (1973).

    Article  CAS  Google Scholar 

  25. Hancock, W.W. et al. Costimulatory function and expression of CD40-ligand, CD80 and CD86 in vascularized murine cardiac allograft rejection. Proc. Natl. Acad. Sci. USA 93, 13967–13972 (1996).

    Article  CAS  Google Scholar 

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Correspondence to Kim M. Olthoff.

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Olthoff, K., Judge, T., Gelman, A. et al. Adenovirus-mediated gene transfer into cold-preserved liver allografts: Survival pattern and unresponsiveness following transduction with CTLA4Ig. Nat Med 4, 194–200 (1998). https://doi.org/10.1038/nm0298-194

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