IL4 Gene Delivery to the CNS Recruits Regulatory T Cells and Induces Clinical Recovery in Mouse Models of Multiple Sclerosis

Gene Ther. 2008 Apr;15(7):504-15. doi: 10.1038/gt.2008.10. Epub 2008 Jan 31.

Abstract

Central nervous system (CNS) delivery of anti-inflammatory cytokines, such as interleukin 4 (IL4), holds promise as treatment for multiple sclerosis (MS). We have previously shown that short-term herpes simplex virus type 1-mediated IL4 gene therapy is able to inhibit experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in mice and non-human primates. Here, we show that a single administration of an IL4-expressing helper-dependent adenoviral vector (HD-Ad) into the cerebrospinal fluid (CSF) circulation of immunocompetent mice allows persistent transduction of neuroepithelial cells and long-term (up to 5 months) CNS transgene expression without toxicity. Mice affected by chronic and relapsing EAE display clinical and neurophysiological recovery from the disease once injected with the IL4-expressing HD-Ad vector. The therapeutic effect is due to the ability of IL4 to increase, in inflamed CNS areas, chemokines (CCL1, CCL17 and CCL22) capable of recruiting regulatory T cells (CD4+CD69-CD25+Foxp3+) with suppressant functions. CSF delivery of HD-Ad vectors expressing anti-inflammatory molecules might represent a valuable therapeutic option for CNS inflammatory disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Central Nervous System / immunology*
  • Central Nervous System / pathology
  • Chemokines / immunology
  • Chemotaxis, Leukocyte
  • Disease Models, Animal
  • Female
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • Green Fluorescent Proteins / analysis
  • Green Fluorescent Proteins / genetics
  • Helper Viruses / genetics
  • Humans
  • Interleukin-4 / analysis
  • Interleukin-4 / genetics*
  • Interleukin-4 / immunology
  • Mice
  • Mice, Inbred C57BL
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology
  • Multiple Sclerosis / therapy*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes, Regulatory / immunology*
  • Transduction, Genetic / methods

Substances

  • Chemokines
  • Green Fluorescent Proteins
  • Interleukin-4