Cytokine therapy in immune-mediated demyelinating diseases of the central nervous system: a novel gene therapy approach.

Abstract

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.

• Authors: G Martino, P L Poliani, R Furlan, P Marconi, J C Glorioso, L Adorini, G Comi
• Journal: Journal of neuroimmunology (J Neuroimmunol) Vol. 107 Issue 2 Pg. 184-90 (Jul 24 2000) ISSN: 0165-5728 [Print] Netherlands
• PMID: 10854655 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CCL2
• Interleukin-4
• Interferon-gamma

Topics

• Animals
• Chemokine CCL2 (genetics)
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental (therapy)
• Genetic Therapy (methods)
• Genetic Vectors
• Herpesvirus 1, Human (genetics)
• Injections, Spinal
• Interferon-gamma (genetics)
• Interleukin-4 (genetics)
• Lac Operon
• Mice
• Mice, Inbred BALB C
• Multiple Sclerosis (therapy)