Induction of specific T-cell tolerance by adenovirus-transfected, Fas ligand - Producing antigen presenting cells

Huana Ge Zhang, Di Liu, Yuji Heike, Pingar Yang, Zheng Wang, Xiaoyun Wang, David T. Curiel, Tong Zhou, John D. Mountz

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

A major problem associated with adenovirus gene therapy is the T cell- mediated immune response, which is elicited by inoculation of the adenovirus vector and leads to rapid clearance of the virus and loss of transgene expression. In this study, the immune response to adenovirus was prevented by induction of specific T-cell tolerance by pretreatment with adenovirus- infected antigen-presenting cells (APC) that express Fas ligand. Compared with control-treated mice, the tolerized mice showed prolonged expression of lacZ upon administration of AdCMVlacZ 1 week after tolerance induction. In contrast to the control mice, the tolerized mice did not display proliferation of CD3°T cells in the spleen in response to AdCMVlacZ. Tolerance induction also was indicated by the lower production of interferon- γ and interleukin-2 by peripheral T cells isolated from AdCMVlacZ-challenged tolerized mice than by AdCMVlacZ-challenged control-treated mice. The T-cell tolerance was specific for the adenovirus as the T-cell responses to irrelative murine cytomegalovirus remained unimpaired. Our results indicate that adenovirus-specific T-cell tolerance can be induced by APCs that coexpress Fas ligand and adenovirus antigens. We propose that this new strategy can be used to induce tolerance to adenovirus vector gene therapy with resultant prolonged expression of the transgene.

Original languageEnglish
Pages (from-to)1045-1049
Number of pages5
JournalNature Biotechnology
Volume16
Issue number11
DOIs
StatePublished - Nov 23 1998
Externally publishedYes

Keywords

  • Apoptosis
  • Gene therapy
  • Immune response

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    Zhang, H. G., Liu, D., Heike, Y., Yang, P., Wang, Z., Wang, X., Curiel, D. T., Zhou, T., & Mountz, J. D. (1998). Induction of specific T-cell tolerance by adenovirus-transfected, Fas ligand - Producing antigen presenting cells. Nature Biotechnology, 16(11), 1045-1049. https://doi.org/10.1038/3488