CENTRAL-NERVOUS-SYSTEM DELIVERY OF INTERLEUKIN-4 BY A NONREPLICATIVE HERPES-SIMPLEX TYPE-1 VIRAL VECTOR AMELIORATES AUTOIMMUNE DEMYELINATION

Multiple sclerosis (MS) is a T cell-mediated organ-specific inflammato ry disease leading to central nervous system (CNS) demyelination. On t he basis of results obtained in experimental autoimmune encephalomyeli tis (EAE) models, MS treatment by administration of antiinflammatory c ytokines such as interleukin 4 (IL-4) is promising but is hampered by the limited access of the cytokines to the CNS and by the pleiotropic effects of systemically administered cytokines. We established a cytok ine delivery system within the CNS using nonreplicative herpes simplex type 1 (HSV-1) viral vectors engineered with cytokine genes. These ve ctors injected into the cisterna magna (i.c.) of mice diffuse in all v entricular and subarachnoid spaces and infect with high efficiency the ependymal and leptomeningeal cell layers surrounding these areas, wit hout obvious toxic effects. Heterologous genes contained in the vector s are efficiently transcribed in infected ependymal cells, leading to the production of high amounts of the coded proteins. For example, 4.5 ng of interferon gamma (IFN-gamma) per milliliter is secreted into th e cerebrospinal fluid (CSF) up to day 28 postinjection (p.i.) and reac hes the CNS parenchyma in bioactive form, as demonstrated by upregulat ion of MHC class I expression on CNS-resident cells. We then exploited the therapeutic potential of the vectors in EAE mice. An HSV-l-derive d vector containing the IL-4 gene was injected i.c. in Biozzi AB/H mic e at the time of EAE induction. We found the following in treated mice : (1) delayed EAE onset, (2) a significant decrease in clinical score, (3) a significant decrease in perivascular inflammatory infiltrates a nd in the number of macrophages infiltrating the CNS parenchyma and th e submeningeal spaces, and (4) a reduction in demyelinated areas and a xonal loss. Peripheral T cells from IL-4-treated mice were not affecte d either in their antigen-specific proliferative response or in cytoki ne secretion pattern. Our results indicate that CNS cytokine delivery with HSV-I vectors is feasible and might represent an approach for the treatment of demyelinating diseases. Advantages of this approach over systemic cytokine administration are the high cytokine level reached in the CNS, the absence of effects on the peripheral immune system, an d the long-lasting cytokine production in the CNS after a single vecto r administration.