Cytokine therapy in immune-mediated demyelinating diseases of the central nervous system: a novel gene therapy approach.
Pro-inflammatory cytokines play a crucial role in the regulatory and effector phase of the immune-mediated mechanism sustaining multiple sclerosis pathogenesis (MS) thus supporting the use of anti-inflammatory cytokines as a therapeutic option. Systemic administration of cytokines shows, however, limited therapeutic efficacy and undesirable/unpredictable side-effects. We have developed a non-toxic system to deliver cytokines within the central nervous system (CNS) based on the intrathecal (i.c.) administration of non-replicative herpes simplex (HSV) type-1-derived viral vectors engineered with heterologous cytokine genes. Compared to controls, mice affected by experimental autoimmune encephalomyelitis (EAE) and i.c. injected with an HSV-1-derived vector containing the gene of the anti-inflammatory cytokine IL-4 showed a significant amelioration of clinical and pathological EAE signs. A decreased mRNA expression of the monocyte chemoattractant protein-1 (MCP-1) by mononuclear CNS-infiltrating cells was also observed. Peripheral T cells from IL-4-treated mice were not affected both in their antigen-specific proliferative response and in the cytokine secretion pattern. Our results indicate that CNS cytokine delivery with HSV-1-derived vectors is a feasible therapeutic strategy and might represent an alternative approach for the treatment of immune-mediated demyelinating diseases. Advantages of this approach over systemic cytokine administration are the high cytokine level reached within the CNS and the absence of side-effects on the peripheral immune system. The short-lasting cytokine production in the CNS after a single vector administration (4 weeks) is the limiting factor of this novel technology which, although promising, has to be improved.
Martino
G
G
Experimental Neuroimmunotherapy Unit, DIBIT - San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. g.martino@hsr.it
Poliani
P L
PL
Furlan
R
R
Marconi
P
P
Glorioso
J C
JC
Adorini
L
L
Comi
G
G
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000235:genetics*; D007278:Injections, Spinal; D007371:Interferon-gamma / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D007763:Lac Operon; D051379:Mice; D008807:Mice, Inbred BALB C; D009103:Multiple Sclerosis / Q000628:therapy*
D018932:Chemokine CCL2; D015847:Interleukin-4; D007371:Interferon-gamma