IL-4 is the key regulator in herpes simplex virus-based gene therapy of BALB/c experimental autoimmune encephalomyelitis.
Local delivery of cytokines or other immunomodulatory components has been applied as a potential therapy for experimental autoimmune encephalomyelitis (EAE), which is used as a model of human multiple sclerosis. We have used herpes simplex virus-based vectors expressing Th2 cytokines IL-4 and IL-10 and have previously shown a significant abolishment of disease symptoms by the virus expressing IL-4 (R8306), but not by the one expressing IL-10 (R8308). In the present study, the aim was to investigate the local and systemic cytokine response after HSV-based gene therapy. We show that the local expression of IL-4 from an HSV vector delivered to the brain converts the cytokine environment from the disease-promoting Th1-prominent to the disease-limiting IL-4 expressing type. We measured the expression of cytokines IL-4, IL-10, IFN-gamma, IL-12p35, IL-12p40 and the novel IL-23p19 from the brain by quantitative LightCycler RT-PCR. We also investigated the systemic cytokine response from the mouse sera. The results indicate that an increase in the Th2 cytokine IL-4 is observed if the diseased mice are treated with IL-4-expressing virus R8306. Surprisingly, the IL-23 expression of R8306 treated mice was at the same level as in the untreated EAE mice. On the contrary, in the R8308 (IL-10 expression) treated mice, the expression of IL-23 was decreased (P < 0.05). We conclude that the favorable effect of IL-4 on the disease development is more important than the downregulation of the Th1 type cytokines (like IL-23), and that IL-4 would be the key mediator of disease abolishment during gene therapy using these vectors.
Broberg
Eeva K
EK
Department of Virology, University of Turku, Kiinamyllynkatu 13, FIN-20520, Finland. eeva.broberg@utu.fi
Salmi
Aimo A
AA
Hukkanen
Veijo
V
D000818:Animals; D001921:Brain / Q000821:virology; D016207:Cytokines / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D015847:Interleukin-4 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus / Q000235:genetics*
D016207:Cytokines; D015847:Interleukin-4