IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis.
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.
Butti
E
E
Neuroimmunology Unit, San Raffaele Scientific Institute, Milan, Italy.
Bergami
A
A
Recchia
A
A
Brambilla
E
E
Del Carro
U
U
Amadio
S
S
Cattalini
A
A
Esposito
M
M
Stornaiuolo
A
A
Comi
G
G
Pluchino
S
S
Mavilio
F
F
Martino
G
G
Furlan
R
R
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology; D018925:Chemokines / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D006378:Helper Viruses / Q000235:genetics; D006801:Humans; D015847:Interleukin-4 / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014161:Transduction, Genetic / Q000379:methods
D018925:Chemokines; D049452:Green Fluorescent Proteins; D015847:Interleukin-4