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Local adenoviral expression of Fas ligand upregulates pro-inflammatory immune responses in the CNS

Gene Therapy volume 11, pages 1462–1474 (2004)Cite this article

Abstract

The central nervous system (CNS) is a site of relative immunological privilege; despite this it can be a target of the immune system under certain conditions. For example, adenoviral vectors elicit an immune response strong enough to result in antigen elimination, in immunologically primed animals. Fas ligand (FasL) contributes to the immune privilege of certain tissues by inducing apoptosis in activated T cells. We therefore investigated whether local overexpression of FasL could downregulate the immune response to adenovirus in the brain. Adenoviral vectors expressing FasL (AdFasL) and the reporter gene β-galactosidase (Adβgal) were co-injected into the striatum of naïve or immunologically primed mice. A co-injection of an adenovirus lacking a transgene (Ad0) and Adβgal acted as a control. At 2 weeks after inoculation, reporter protein expression was significantly reduced with the AdFasL:Adβgal combination compared with the Ad0:Adβgal controls. This was accompanied by a strong inflammatory cell infiltrate, local demyelination and upregulation of pro-inflammatory cytokine gene expression. These experiments demonstrate that FasL overexpression elicits a pro-inflammatory response in the CNS rather than immunosuppression. This was characterized by chronic inflammation and accelerated loss of transgene expression. Induction of such an unexpected pro-inflammatory response caused by introducing FasL may be a peculiarity of the relative immunoprivilege of the unique environment of the brain.

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Acknowledgements

This work was supported by The Wellcome Trust (UK). ELR was the recipient of a Wellcome Prize Studentship. We are particularly grateful to Dr Libermann for the generous gift of the FasL adenovirus.

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  1. Department of Human Anatomy and Genetics, University of Oxford, Oxford, OX1 3QX, UK

    EL Regardsoe, MM McMenamin, HM Charlton & MJA Wood

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Regardsoe, E., McMenamin, M., Charlton, H. et al. Local adenoviral expression of Fas ligand upregulates pro-inflammatory immune responses in the CNS. Gene Ther 11, 1462–1474 (2004). https://doi.org/10.1038/sj.gt.3302322

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