Local LIF Production in the CNS Limits Autoimmune Demyelination

Abstract

Multiple sclerosis is a demyelinating disease of the central nervous system (CNS) with an inflammatory and a neurodegenerative component. The neuropoietic cytokine leukemia inhibitory factor (LIF) is expressed in MS lesions, but its effect on lesion development is far from understood. LIF is suggested to be an interesting candidate for MS therapy, as it has neuroprotecive properties and may also promote survival of myelinating oligodendrocytes. However, therapeutic administration of LIF is complicated by its limited ability to cross the blood-brain barrier and its pleiotropic actions outside the CNS. To circumvent these problems, we used lentiviral vectors to achieve a stable expression and secretion of LIF in the CNS of adult mice. Gene therapeutic expression of LIF in the CNS significantly reduced immune-mediated demyelination and ameliorated EAE symptoms with enhanced efficacy compared to systemic treatment. These findings demonstrate that local LIF production is a promising therapeutic option to limit lesion progression in neuroinflammatory disease.