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Transcriptional targeting of DCs with lentiviral vectors induces antigen-specific tolerance in a mouse model of multiple sclerosis

Gene Therapy volume 20, pages 556–566 (2013)Cite this article

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Abstract

The aim of this work was to induce permanent tolerance toward self-antigens involved in autoimmune diseases, such as multiple sclerosis (MS). We hypothesized that the stable auto-antigen presentation by dendritic cells (DCs) would tolerize auto-reactive T cells and, therefore, prevent disease development in a mouse model of experimental autoimmune encephalomyelitis (EAE), which closely resembles MS. Specifically, our strategy included the ex vivo modification of hematopoietic stem cells (HSCs) with self-inactivating (SIN) lentivirus vectors that transcriptionally target the expression of myelin antigens to DCs. As SIN lentivirus vectors support the genomic integration of transgene sequences in HSC, the transduced and transplanted HSC may provide a constant supply of antigen expressing steady-state DCs. Here, we demonstrate that targeting myelin oligodendrocyte glycoprotein (MOG) expression to DCs indeed resulted in complete and stable protection from EAE. No histological signs of EAE, such as demyelination, axonal damage, or infiltration of leukocytes in brain, spinal cord and optical nerve, were observed in tolerized mice. Tolerance induction was concomitant with the efficient deletion of MOG-specific T cells and the generation of Foxp3+ regulatory T cells and, most importantly, directed toward a specific self-antigen while T-cell reactivity to unrelated foreign antigens was fully preserved.

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Acknowledgements

We thank Burkhard Becher, Martin Pruschy, Carla Rohrer-Bley and Kati Zlinszky for scientific and technical support, Dana Salathe and Maricello Rios for assistance with mice, and Craig Chappell for helpful comments on this manuscript. This work was supported by funds from the Swiss Multiple Sclerosis Society and the University of Zurich.

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  1. C Dresch

    Present address: 3Current address: Department of Immunology, University of Washington, Seattle, WA, USA.,

Authors and Affiliations

  1. Institute of Virology, University of Zurich, Zurich, Switzerland

    B de Andrade Pereira, C Fraefel, M Ackermann & C Dresch

  2. Institute of Veterinary Pathology, University of Zurich, Zurich, Switzerland

    M Hilbe

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  1. B de Andrade Pereira
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  2. C Fraefel
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Correspondence to C Fraefel.

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de Andrade Pereira, B., Fraefel, C., Hilbe, M. et al. Transcriptional targeting of DCs with lentiviral vectors induces antigen-specific tolerance in a mouse model of multiple sclerosis. Gene Ther 20, 556–566 (2013). https://doi.org/10.1038/gt.2012.73

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