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Gene transfer to the thymus. A means of abrogating the immune response to recombinant adenovirus.

Publication ,  Journal Article
DeMatteo, RP; Raper, SE; Ahn, M; Fisher, KJ; Burke, C; Radu, A; Widera, G; Claytor, BR; Barker, CF; Markmann, JF
Published in: Ann Surg
September 1995

OBJECTIVE: The authors investigated whether adenoviral gene transfer to the thymus could be accomplished in vivo and whether immunologic unresponsiveness to recombinant adenovirus could be induced by intrathymic inoculation. SUMMARY BACKGROUND DATA: A major barrier to the clinical application of adenovirus-mediated gene therapy for diseases requiring long-lasting gene expression is the immunogenicity of adenoviral vectors, which limits the duration of its effects. In other experimental models, intrathymic inoculation of foreign proteins or cells has proven to be an effective means to induce immunologic tolerance. METHODS: The efficiency of gene transfer to the mouse thymus after direct inoculation of recombinant adenovirus was compared with that of several other vectors. Animals inoculated with adenovirus-infected pancreatic islets into the thymus were tested for unresponsiveness to the virus with a subsequent challenge of adenovirus administered into the liver by intravenous injection. RESULTS: Adenovirus accomplished highly efficient gene transfer to the thymus, unlike plasmid DNA, DNA-liposome complexes, retrovirus, and adeno-associated virus. Adenoviral transgene expression was transient in the thymus of immunocompetent mice but persistent in CD8+ T-cell-deficient and severe combined immunodeficiency (SCID) mice, implicating the role of cytotoxic T lymphocytes in viral clearance. Intrathymic transplantation of syngeneic pancreatic islet cells infected with adenovirus impaired the normal antiviral cytotoxic T-lymphocyte response and prolonged hepatic transgene expression after an intravenous challenge with adenovirus. CONCLUSIONS: Recombinant adenovirus accomplishes highly efficient gene transfer to the thymus in vivo. Intrathymic inoculation of adenovirus-infected islets can be used to induce immunologic unresponsiveness to the adenoviral vector and, potentially, to other proteins that it might be engineered to encode.

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Published In

Ann Surg

DOI

ISSN

0003-4932

Publication Date

September 1995

Volume

222

Issue

3

Start / End Page

229 / 239

Location

United States

Related Subject Headings

  • Thymus Gland
  • T-Lymphocytes, Cytotoxic
  • Surgery
  • Plasmids
  • Mice, Inbred C57BL
  • Mice
  • Lac Operon
  • Islets of Langerhans
  • Immune Tolerance
  • Gene Transfer Techniques
 

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DeMatteo, R. P., Raper, S. E., Ahn, M., Fisher, K. J., Burke, C., Radu, A., … Markmann, J. F. (1995). Gene transfer to the thymus. A means of abrogating the immune response to recombinant adenovirus. Ann Surg, 222(3), 229–239. https://doi.org/10.1097/00000658-199509000-00002
DeMatteo, R. P., S. E. Raper, M. Ahn, K. J. Fisher, C. Burke, A. Radu, G. Widera, B. R. Claytor, C. F. Barker, and J. F. Markmann. “Gene transfer to the thymus. A means of abrogating the immune response to recombinant adenovirus.Ann Surg 222, no. 3 (September 1995): 229–39. https://doi.org/10.1097/00000658-199509000-00002.
DeMatteo RP, Raper SE, Ahn M, Fisher KJ, Burke C, Radu A, et al. Gene transfer to the thymus. A means of abrogating the immune response to recombinant adenovirus. Ann Surg. 1995 Sep;222(3):229–39.
DeMatteo, R. P., et al. “Gene transfer to the thymus. A means of abrogating the immune response to recombinant adenovirus.Ann Surg, vol. 222, no. 3, Sept. 1995, pp. 229–39. Pubmed, doi:10.1097/00000658-199509000-00002.
DeMatteo RP, Raper SE, Ahn M, Fisher KJ, Burke C, Radu A, Widera G, Claytor BR, Barker CF, Markmann JF. Gene transfer to the thymus. A means of abrogating the immune response to recombinant adenovirus. Ann Surg. 1995 Sep;222(3):229–239.

Published In

Ann Surg

DOI

ISSN

0003-4932

Publication Date

September 1995

Volume

222

Issue

3

Start / End Page

229 / 239

Location

United States

Related Subject Headings

  • Thymus Gland
  • T-Lymphocytes, Cytotoxic
  • Surgery
  • Plasmids
  • Mice, Inbred C57BL
  • Mice
  • Lac Operon
  • Islets of Langerhans
  • Immune Tolerance
  • Gene Transfer Techniques