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 naive or immunologically primed mice. A co-injection of an adenovirus lacking a transgene (Ad0) and Adbgal 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.