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

Gianvito Martino, Pietro L. Poliani, Roberto Furlan, Peggy Marconi, Joseph C. Glorioso, Luciano Adorini, Giancarlo Comi

Research output: Contribution to journalArticle

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. (C) 2000 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)184-190
Number of pages7
JournalJournal of Neuroimmunology
Volume107
Issue number2
DOIs
Publication statusPublished - Jul 24 2000

Keywords

  • Cytokines
  • Experimental autoimmune encephalomyelitis
  • Gene therapy
  • Herpes simplex type-1- derived viral vectors
  • Inflammation
  • Multiple sclerosis

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Clinical Neurology
  • Neurology

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