Antigen-specific therapy of EAE via intranasal delivery of filamentous phage displaying a myelin immunodominant epitope

Abstract 

The presence of anti-myelin antibodies (Abs) in patients with early multiple sclerosis (MS) and in MS animal models has led to renewed interest in the role of B cells, plasma cells and their products in the pathogenesis of the disease, and in their therapeutic potential. Here, we present a novel strategy based on filamentous phage display of the myelin oligodendrocyte glycoprotein immunodominant epitope (MOG 36–44) fused to the main coat protein. Filamentous phages are well characterized, both structurally and genetically. We found that the fibrous shape of the phage (1000nm long and 6nm wide) enables penetration into the central nervous system (CNS) when administered nasally. Thus, intranasal treatment of experimental autoimmune encephalomyelitis (EAE) in mice, with phage MOG, showed improved neuronal function, reduced levels of proinflammatory cytokines, particularly monocyte chemoattractant protein 1 (MCP-1), interferon γ (IFN-γ) and IL-6, but no change in IL-10 or IL-12 levels. Moreover, the treatment induced depletion of the autoantibodies against MOG and prevented demyelination resulting in improved clinical scores and the reduced inflammation in the CNS and periphery in EAE mice compared to untreated sick animals.

Abbreviations: EAE, experimental autoimmune encephalomyelitis, CNS, central nervous system, MS, multiple sclerosis, Ig, immunoglobulin, MOG, myelin oligodendrocyte glycoprotein, MCP-1, monocyte chemoattractant protein 1, i.p, intraperitoneal, i.n, intranasal, IFNγ, interferon-γ, IL, interleukin, TNF, tumor necrosis factor, LFB, Luxol fast blue, GFAP, Glial fibrillary acidic protein, CSF, cerebrospinal fluid, scFv, single-chain variable fragment

Keywords: Multiple sclerosis, Antigen-specific therapy, Phage therapy, Experimental autoimmune encephalomyelitis, Monocyte chemoattractant protein 1, Autoantibodies