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Long–term hepatic adenovirus–mediated gene expression in mice following CTLA4Ig administration

Abstract

Recombinant adenovirus vectors are efficient at transferring genes into somatic tissues but are limited for use in clinical gene therapy by immunologic factors that result in the rapid loss of gene expression and inhibit secondary gene transfer. This study demonstrates that systemic coadministration of recombinant adenovirus with soluble CTLA4lg, which is known to block co–stimulatory signals between T cells and antigen presenting cells, leads to persistent adenoviral gene expression in mice without long–term immunosuppression. This form of immunotherapy greatly enhances the likelihood that recombinant adenovirus vectors will be useful for human gene therapy.

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References

  1. Kay, M.A. & Woo, S.L.C. Gene therapy for metabolic disorders. Trends Genet. 10, 253–257 (1994).

    Article  CAS  Google Scholar 

  2. Li, Q., Kay, M.A., Finegold, M., Stratford-Perricaudet, L.D. & Woo, S.L.C. Assessment of recombinant adenoviral vectors for hepatic gene therapy. Hum. Gene Ther. 4, 403–408 (1993).

    Article  CAS  Google Scholar 

  3. Kay, M.A. et al. In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs. Proc. natn. Acad. Sci. U.S.A. 91, 2353–2357 (1994).

    Article  CAS  Google Scholar 

  4. Ishibashi, S. et al. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin. Invest. 92, 883–893 (1993).

    Article  CAS  Google Scholar 

  5. Kozarsky, K.F. et al. In vivo correction of low density lipoprotein receptor deficiency in the Watanabe heritable hyperlipidemic rabbit with recombinant adenoviruses. J. biol. Chem. 269, 13695–13702 (1994).

    CAS  Google Scholar 

  6. Yang, Y. et al. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc. natn. Acad. Sci. U.S.A. 91, 4407–4411 (1994).

    Article  CAS  Google Scholar 

  7. Yang, Y., Ertl, H.C.J. & Wilson, J.M. MHC class l-restricted cytotoxic T lymphocytes to viral antigens destroy hepatocytes in mice infected with E1-deleted recombinant adenoviruses. Immunity 1, 433–442 (1994).

    Article  CAS  Google Scholar 

  8. Smith, T.A. et al. Adenovirus mediated expression of therapeutic plasma levels of human factor IX in mice. Nature Genet. 5, 397–402 (1993).

    Article  CAS  Google Scholar 

  9. Barr, D. et al. Strain related variations in adenovirally mediated transgene expression in mouse hepatocytes in vivo: comparisons between immunocompetent and immunodeficient inbred strains. Gene Ther. 2, 151–155 (1995).

    CAS  PubMed  Google Scholar 

  10. Englehardt, J.F., Ye, X., Doranz, B. & Wilson, J.M. Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver. Proc. natn. Acad. Sci. U.S.A. 91, 6196–6200 (1994).

    Article  Google Scholar 

  11. Hathcock, K.S. et al. Identification of an alternative CTLA4 ligand costimulatory for T cell activation. Science 262, 905–907 (1993).

    Article  CAS  Google Scholar 

  12. Azuma, M. et al. B70 antigen is a second ligand for CTLA-4 and CD28. Nature 366, 76–79 (1993).

    Article  CAS  Google Scholar 

  13. Linsley, P.S. & Ledbetter, J.A. The role of the CD28 receptor during T cell responses to antigen. A. Rev. Immunol. 11, 191–212 (1993).

    Article  CAS  Google Scholar 

  14. Freeman, G. et al. Cloning of B7-2: a CTLA4 counter-receptor that costimulates human T cell proliferation. Science 262, 909–911 (1993).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Lenschow, D.J. et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science 257, 789–792.

    Article  CAS  Google Scholar 

  17. Finck, B.K., Linsley, P.S. & Wofsy, D. Treatment of murine lupus with CTLA4lg. Science 265, 1225–1227 (1994).

    Article  CAS  Google Scholar 

  18. Kay, M.A., Graham, F., Leland, F. & Woo, S.L.C. Therapeutic serum concentrations of serum alpha 1-antitrypsin after adenoviral-mediated gene transfer to mouse hepatocytes in vivo. Hepatology 21, 815–819 (1995).

    CAS  PubMed  Google Scholar 

  19. Kay, M.A. et al. Hepatic gene therapy: persistent expression of human alpha 1-antitrypsin in mice after direct gene delivery in vivo. Hum. Gene Ther. 3, 641–647 (1992).

    Article  CAS  Google Scholar 

  20. Ponder, K.P. et al. Mouse heptocytes migrate to liver parenchyma and function indefinetely after intrasplenic transplantation. Proc. natn. Acad. Sci. U.S.A. 88, 1217–1221 (1991).

    Article  CAS  Google Scholar 

  21. Dai, Y. et al. Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: Tolerization of factor IX and vector antigens allows for long-term expression. Proc. natn. Acad. Sci. U.S.A. 92, 1401–1405 (1995).

    Article  CAS  Google Scholar 

  22. Rinaldo, C.R. & Torpey, D.J. III. Cell-mediated immunity and immunosuppression in herpes simplex virus infection. Immunodeficiency 5, 33–90 (1993).

    PubMed  Google Scholar 

  23. Simmons, A. & Tscharke, D.C. Anti-CD8 impairs clearance of herpes simplex virus from the nervous system: implications for the fate of virally infected neurons. J. exp. Med. 175, 1337–1244 (1992).

    Article  CAS  Google Scholar 

  24. Shahinan, A. et al. Differential T cell costimulatory requirements in CD28-deficient mice. Science 261, 609–612 (1993).

    Article  Google Scholar 

  25. Bluestone, J.A. New perspectives of CD28-B7-mediated T cell costimulation. Immunity 2, 555–559 (1995).

    Article  CAS  Google Scholar 

  26. Nonoyama, S., Smith, F.O., Bernstein, I.D. & Ochs, H.D. Strain dependent leakiness of mice with severe combined immune deficiency. J. Immunol. 150, 3817–3824 (1993).

    CAS  PubMed  Google Scholar 

  27. Nonoyama, S., Hollenbaugh, D., Aruffo, A., Ledbetter, J.A. & Ochs, H.D. B cell activation via CD40 is required for specific antibody production by antigen stimulated human B cells. J. exp. Med. 178, 1097–1102 (1993).

    Article  CAS  Google Scholar 

  28. Paul, W.A. & Seder, W.E. Lymphocyte responses and cytokines. Cell 76, 241–251 (1994).

    Article  CAS  Google Scholar 

  29. Nguyen, L., Knipe, D.M. & Finberg, R.W. Mechanism of virus-induced Ig subclass shifts. J. Immunol. 152, 478–484 (1994).

    CAS  PubMed  Google Scholar 

  30. Scaria, A., Curiel, D. & Kay, M.A. Complementation of a human adenovirus early region 4 deletion mutant in 293 cells using adenovirus-polylysine-DNA complexes. Gene Ther. 2, 295–298 (1995).

    CAS  PubMed  Google Scholar 

  31. Rawle, F.C. et al. Specificity of the mouse cytotoxic T lymphocytes response to adenovirus 5. J. Immunol 146, 3977–3984 (1991).

    CAS  PubMed  Google Scholar 

  32. Knodell, R.G. et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1, 431–435 (1981).

    Article  CAS  Google Scholar 

  33. Lewis, D.B. et al. Interleukin 4 expressed in situ selectively alters thymocyte development J. exp. Med. 173, 89–100 (1994).

    Article  Google Scholar 

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Kay, M., Holterman, AX., Meuse, L. et al. Long–term hepatic adenovirus–mediated gene expression in mice following CTLA4Ig administration. Nat Genet 11, 191–197 (1995). https://doi.org/10.1038/ng1095-191

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