Local adenoviral expression of Fas ligand upregulates pro-inflammatory immune responses in the CNS.
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 beta-galactosidase (Adbetagal) were co-injected into the striatum of naïve or immunologically primed mice. A co-injection of an adenovirus lacking a transgene (Ad0) and Adbetagal acted as a control. At 2 weeks after inoculation, reporter protein expression was significantly reduced with the AdFasL:Adbetagal combination compared with the Ad0:Adbetagal 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.
Regardsoe
E L
EL
Department of Human Anatomy and Genetics, University of Oxford, OX1 3QX, UK.
McMenamin
M M
MM
Charlton
H M
HM
Wood
M J A
MJ
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology*; D017209:Apoptosis; D001921:Brain / Q000276:immunology* / Q000473:pathology; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics; D004660:Encephalitis / Q000276:immunology* / Q000473:pathology; D053222:Fas Ligand Protein; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000473:pathology; D019076:Transgenes; D001616:beta-Galactosidase / Q000235:genetics
D000956:Antigens, Viral; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D001616:beta-Galactosidase