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 effect or phase of the immune-mediated mechanism sustaining multiple sclerosis pat hogenesis (MS thus supporting the use of anti-inflammatory cytokines as a t herapeutic option. Systemic administration of cytokines shows. however. lim ited therapeutic efficacy and undesirable/unpredictable side-effects. We ha ve developed a non-toxic system to deliver cytokines within the central ner vous system (CNS based on the intrathecal (i.c.) administration of non-repl icative herpes simplex (HSV) type-1-derived viral vectors engineered with h eterologous cytokine genes. Compared to controls, mice affected by experime ntal autoimmune encephalomyelitis (EAE) and i.c. injected with an HSV-1-der ived vector containing the gene ai the anti-inflammatory cytokine IL-4 show ed a significant amelioration of clinical and pathological EAE signs. A dec reased mRNA expression of the monocyte chemoattractant protein-1 (MCP-1) by mononuclear CNS-infiltrating cells was also observed. Peripheral T cells f rom IL-4-treated mice were not affected both in their antigen-specific prol iferative response and in the cytokine secretion pattern. Our results indic ate that CNS cytokine deliver?: with HSV-1-derived vectors is a feasible th erapeutic strategy and might represent an alternative approach for the trea tment of immune-mediated demyelinating diseases. Advantages of this approac h over systemic cytokine administration are the high cytokine level reached within the CNS and the absence of side-effects on the peripheral immune sy stem. The short-lasting cytokine production in the CNS after a single vecto r administration (4 weeks) is the limiting factor of this novel technology which. although promising, has to be improved. (C) 2000 Elsevier Science B. V. All rights reserved.