Medicine

Multiple sclerosis (MS) is considered to be a T cell-mediated autoimmune disease directed against myelinated nerves within the central nervous system. Current therapies available to MS patients have low efficacy and are immunosuppressive. Novel therapies that negatively regulate or delete autoreactive T cells, i.e., induce antigen-specific T cell tolerance, are key for the development of more efficacious and perhaps curative therapies. Our laboratory has developed a vaccine platform comprised of cytokine-antigen fusion proteins to promote T cell tolerance. In this study, GM-CSF and M-CSF cytokines were tested as domains in cytokine-neuroantigen (NAg) fusion proteins to assess targeting of NAg to different antigen presenting cell (APC) subsets. Fusion proteins were designed with a cytokine N-terminal domain and the encephalitogenic peptide 69-88 of guinea pig myelin basic protein (GP69-88) as the C-terminal domain. Studies measuring T cell activation in vitro, prevention of experimental autoimmune encephalomyelitis (EAE), and treatment of EAE showed that GMCSF-NAg was the most potent fusion protein, with the following rank order of activity (GMCSF-NAg> MCSF-NAg> GP69-88). GMCSF-NAg was 1000-fold more potent than GP69-88 in stimulating myelin basic protein (MBP)-specific T cell proliferation. Th