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

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 b-galactosidase (Adbgal) were co-injected into the striatum of naïve 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:Adbgal combination compared with the Ad0:Adbgal 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.

Inflammation, Apoptosis, and Necrosis Induced by Neoadjuvant Fas Ligand Gene Therapy Improves Survival of Dogs With Spontaneous Bone Cancer

“…17 The adenovirus-mediated expression of FasL also is abrogated in a relatively short time (~14 days) because the transduced cells are killed as a consequence of the inflammatory response. 33 Therefore, both mechanisms (Fas-mediated apoptosis and inflammation leading to tumor cell death) minimize persistence of FasL in the system. The most commonly observed toxicities were transient increases in aspartate transaminase and creatine phosphokinase.…”

In vitro apoptotic induction of human glioblastoma cells by Fas ligand plus etoposide and in vivo antitumour activity of combined drugs in xenografted nude rats

“…However, marked inflammatory lesions were detected mostly in the surrounding areas of tumours in animals treated with the combination of FasL and etoposide and not in untreated rats. These lesions could be related to the inflammatory activity of FasL through chemokines and IL-1 release (33)(34)(35).…”

IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis

“…3,4 Systemic as well as intraparenchymal delivery of viral vectors usually induces humoral and cell-mediated immune responses against the vectors and/or transgene products, leading to inflammation, short-term persistence of gene expression and elimination of transduced cells. [5][6][7] We, and others, have previously shown that injection of viral vectors into the cisterna magna, or trough lumbar puncture, might represent an efficient CNS delivery system in both small (mice) and large (non-human primates) animals. [8][9][10][11] Administration of vector into the cerebrospinal fluid (CSF) circulation, while bypassing the blood-brain barrier, allows viral vector transduction of neuroepithelial cells and delivery of transgene products to the whole CNS through the ventricular circulation.…”