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

Nature Biotechnology volume 16, pages 1045–1049 (1998)Cite this article

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-g 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.

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Figure 1: FasL production by APCs.
Figure 2: AdlacZ transgene expression after APC-AdfasL followed by AdCMVlacZ.
Figure 3: Splenic T cells after APC-AdfasL followed by AdCMVLacZ. Wild-type C57BL/6 mice were treated with 1 × 106 of (A) APC, (B) APC-AdControl, (C) APC-AdfasL every 3 days until five doses were given and challenged with AdCMVlacZ (1 × 1010 pfu).
Figure 4: Migration of APC-AdCMVGFP in vivo.
Figure 5: Cytotoxic T-cell response to APC + Ad after APC-AdfasL.
Figure 6: Cytokine production by T cells stimulated with APC + Ad after APC-Ad fasL.
Figure 7: IL-2 production by T cells stimulated with APC + MCMV after APC-Ad fasL.

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Acknowledgements

This work was supported in part by VA Career Development and Merit Review Award, National Institutes of Health Grants NO1-AR-6-2224 and RO1-AR-42547 from NIAMS to J.D.M., and by a grant from Sankyo, Inc. T.Z. is the recipient of an Arthritis Foundation Investigator Award.

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Authors and Affiliations

  1. Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, 35294, AL

    Huang-Ge Zhang, Di Liu, PingAr Yang, Zheng Wang, Xiaoyun Wang, Tong Zhou & John D. Mountz

  2. Gene Therapy Program, University of Alabama at Birmingham , Birmingham, 35294, AL

    Yuji Heike & David T. Curiel

  3. Veterans Administration Medical Center, Birmingham, 35233, AL

    John D. Mountz

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  1. Huang-Ge Zhang
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Correspondence to John D. Mountz.

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Zhang, HG., Liu, D., Heike, Y. et al. Induction of specific T-cell tolerance by adenovirus-transfected, Fas ligand-producing antigen-presenting cells. Nat Biotechnol 16, 1045–1049 (1998). https://doi.org/10.1038/3488

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