Endothelial Cells as Gene Vehicles for MS Therapy

DESCRIPTION (provided by the applicant): It is generally accepted that autoreactive T cells are involved in pathogenesis of multiple sclerosis (MS). We have shown that CD24 gene controls the effector function, but not the induction, of the autoreactive T cells in the mouse model of multiple sclerosis, the experimental autoimmune encephalomyelitis. We have also shown that injection of fusion protein comprising of the extracellular domain of the CD24 protein results in significant reduction in the clinical score of the EAE. More recently, we discovered that in bone marrow chimera mice, bone marrow-derived cells could replace the vascular endothelial cells in the CNS. To explore the potential clinical application of these observations to the therapy of multiple sclerosis, we have established novel in vitro culture protocol to produce bone marrow-derived endothelial cells. We have found that they can migrate into the CNS after adoptive transfer and form neovasculature in the CNS. Moreover, we have produced lentiviral vector that can transduce the CD24Ig gene into the endothelial cells in vitro. In this proposal, we will test whether the endothelial cells expressing CD24Ig can be used for the therapy of EAE in mouse model. Specifically, we will address two questions: 1). Are mice reconstituted with endothelial cells expressing CD24Ig resistant to pathogenic autoreactive T cells in CNS? We will transduce bone marrow derived endothelial cells from C57BL/6 mice with CD24Ig gene and test whether injection of the CD24Ig-transduced endothelial cells will result in resistance to autoreactive T cells. We will also compare the efficacy of CD24IgG to that of CD241gM that should have higher valences and therefore may have higher avidity for the potential CD24 ligands. 2). Can the CD24Ig-transduced endothelial cells provide therapeutic effect in mice with relapsing remitting EAE? We will transduce bone marrow derived endothelial cells from SJL mice with CD24Ig gene. We will inject the CD24Ig-transduced endothelial cells into SJL mice with ongoing EAE and test if these cells can prevent EAE relapse. Our proposed work will test the concept of using endothelial cells as a gene vehicle for the treatment of multiple sclerosis. If succeed, this will provide a new approach for therapy of organ-specific autoimmune diseases in general and the multiple sclerosis in particular.