Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1997 Jul;71(7):5330–5335. doi: 10.1128/jvi.71.7.5330-5335.1997

Long-lasting adenovirus transgene expression in mice through neonatal intrathymic tolerance induction without the use of immunosuppression.

R P DeMatteo 1, G Chu 1, M Ahn 1, E Chang 1, C F Barker 1, J F Markmann 1
PMCID: PMC191770  PMID: 9188602

Abstract

The major barrier to the clinical application of adenovirus gene therapy for diseases that require stable transgene expression is the immunogenicity of recombinant adenovirus, which ordinarily limits the duration of its effects to a period of about 2 weeks. We postulated that tolerance to adenovirus could be induced and transgene expression could be prolonged if T lymphocytes underwent thymic selection in the presence of adenovirus antigens. Mice were inoculated in the thymus with a recombinant adenovirus containing the lacZ marker gene during the neonatal period at a time before T-cell maturation had occurred. When the virus was administered intravenously to these mice in adulthood, they were found to have an impaired adenovirus-specific cytotoxic T-lymphocyte response which allowed prolonged hepatic lacZ expression, for up to 260 days. The ability to achieve unresponsiveness to a recombinant adenovirus after inoculation of the thymus in neonates extends the paradigm of intrathymic tolerance induction. Furthermore, this model will enable the study of stable adenovirus transgene expression in vivo without the use of immunosuppression and ultimately may have clinical utility.

Full Text

The Full Text of this article is available as a PDF (472.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adzick N. S., Harrison M. R. Fetal surgical therapy. Lancet. 1994 Apr 9;343(8902):897–902. doi: 10.1016/s0140-6736(94)90012-4. [DOI] [PubMed] [Google Scholar]
  2. Cihak J., Lehmann-Grube F. Immunological tolerance to lymphocytic choriomeningitis virus in neonatally infected virus carrier mice: evidence supporting a clonal inactivation mechanism. Immunology. 1978 Feb;34(2):265–275. [PMC free article] [PubMed] [Google Scholar]
  3. Crystal R. G. Transfer of genes to humans: early lessons and obstacles to success. Science. 1995 Oct 20;270(5235):404–410. doi: 10.1126/science.270.5235.404. [DOI] [PubMed] [Google Scholar]
  4. Dai Y., Schwarz E. M., Gu D., Zhang W. W., Sarvetnick N., Verma I. M. 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 Natl Acad Sci U S A. 1995 Feb 28;92(5):1401–1405. doi: 10.1073/pnas.92.5.1401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. DeMatteo R. P., Markmann J. F., Kozarsky K. F., Barker C. F., Raper S. E. Prolongation of adenoviral transgene expression in mouse liver by T lymphocyte subset depletion. Gene Ther. 1996 Jan;3(1):4–12. [PubMed] [Google Scholar]
  6. DeMatteo R. P., Raper S. E., Ahn M., Fisher K. J., Burke C., Radu A., Widera G., Claytor B. R., Barker C. F., Markmann J. F. Gene transfer to the thymus. A means of abrogating the immune response to recombinant adenovirus. Ann Surg. 1995 Sep;222(3):229–242. doi: 10.1097/00000658-199509000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Engelhardt 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 Natl Acad Sci U S A. 1994 Jun 21;91(13):6196–6200. doi: 10.1073/pnas.91.13.6196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Forsthuber T., Yip H. C., Lehmann P. V. Induction of TH1 and TH2 immunity in neonatal mice. Science. 1996 Mar 22;271(5256):1728–1730. doi: 10.1126/science.271.5256.1728. [DOI] [PubMed] [Google Scholar]
  9. Haj-Ahmad Y., Graham F. L. Development of a helper-independent human adenovirus vector and its use in the transfer of the herpes simplex virus thymidine kinase gene. J Virol. 1986 Jan;57(1):267–274. doi: 10.1128/jvi.57.1.267-274.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ilan Y., Attavar P., Takahashi M., Davidson A., Horwitz M. S., Guida J., Chowdhury N. R., Chowdhury J. R. Induction of central tolerance by intrathymic inoculation of adenoviral antigens into the host thymus permits long-term gene therapy in Gunn rats. J Clin Invest. 1996 Dec 1;98(11):2640–2647. doi: 10.1172/JCI119085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kass-Eisler A., Falck-Pedersen E., Elfenbein D. H., Alvira M., Buttrick P. M., Leinwand L. A. The impact of developmental stage, route of administration and the immune system on adenovirus-mediated gene transfer. Gene Ther. 1994 Nov;1(6):395–402. [PubMed] [Google Scholar]
  12. Kay M. A., Holterman A. X., Meuse L., Gown A., Ochs H. D., Linsley P. S., Wilson C. B. Long-term hepatic adenovirus-mediated gene expression in mice following CTLA4Ig administration. Nat Genet. 1995 Oct;11(2):191–197. doi: 10.1038/ng1095-191. [DOI] [PubMed] [Google Scholar]
  13. King C. C., Jamieson B. D., Reddy K., Bali N., Concepcion R. J., Ahmed R. Viral infection of the thymus. J Virol. 1992 May;66(5):3155–3160. doi: 10.1128/jvi.66.5.3155-3160.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kozarsky K. F., Wilson J. M. Gene therapy: adenovirus vectors. Curr Opin Genet Dev. 1993 Jun;3(3):499–503. doi: 10.1016/0959-437x(93)90126-a. [DOI] [PubMed] [Google Scholar]
  15. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991–1045. doi: 10.1146/annurev.iy.12.040194.005015. [DOI] [PubMed] [Google Scholar]
  16. Mulligan R. C. The basic science of gene therapy. Science. 1993 May 14;260(5110):926–932. doi: 10.1126/science.8493530. [DOI] [PubMed] [Google Scholar]
  17. Posselt A. M., Barker C. F., Friedman A. L., Naji A. Prevention of autoimmune diabetes in the BB rat by intrathymic islet transplantation at birth. Science. 1992 May 29;256(5061):1321–1324. doi: 10.1126/science.1598576. [DOI] [PubMed] [Google Scholar]
  18. Posselt A. M., Barker C. F., Tomaszewski J. E., Markmann J. F., Choti M. A., Naji A. Induction of donor-specific unresponsiveness by intrathymic islet transplantation. Science. 1990 Sep 14;249(4974):1293–1295. doi: 10.1126/science.2119056. [DOI] [PubMed] [Google Scholar]
  19. Ridge J. P., Fuchs E. J., Matzinger P. Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science. 1996 Mar 22;271(5256):1723–1726. doi: 10.1126/science.271.5256.1723. [DOI] [PubMed] [Google Scholar]
  20. Sarzotti M., Robbins D. S., Hoffman P. M. Induction of protective CTL responses in newborn mice by a murine retrovirus. Science. 1996 Mar 22;271(5256):1726–1728. doi: 10.1126/science.271.5256.1726. [DOI] [PubMed] [Google Scholar]
  21. Stratford-Perricaudet L. D., Levrero M., Chasse J. F., Perricaudet M., Briand P. Evaluation of the transfer and expression in mice of an enzyme-encoding gene using a human adenovirus vector. Hum Gene Ther. 1990 Fall;1(3):241–256. doi: 10.1089/hum.1990.1.3-241. [DOI] [PubMed] [Google Scholar]
  22. 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. Nat Med. 1996 May;2(5):545–550. doi: 10.1038/nm0596-545. [DOI] [PubMed] [Google Scholar]
  23. Yang Y., Ertl H. C., Wilson J. M. MHC class I-restricted cytotoxic T lymphocytes to viral antigens destroy hepatocytes in mice infected with E1-deleted recombinant adenoviruses. Immunity. 1994 Aug;1(5):433–442. doi: 10.1016/1074-7613(94)90074-4. [DOI] [PubMed] [Google Scholar]
  24. Yang Y., Nunes F. A., Berencsi K., Furth E. E., Gönczöl E., Wilson J. M. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4407–4411. doi: 10.1073/pnas.91.10.4407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Yang Y., Xiang Z., Ertl H. C., Wilson J. M. Upregulation of class I major histocompatibility complex antigens by interferon gamma is necessary for T-cell-mediated elimination of recombinant adenovirus-infected hepatocytes in vivo. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7257–7261. doi: 10.1073/pnas.92.16.7257. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES