Antigen-specific therapy of EAE via intranasal delivery of filamentous phage displaying a myelin immunodominant epitope.
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 (1000 nm long and 6 nm 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 gamma (IFN-gamma) 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.
Rakover
Idan S
IS
Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv, Tel-Aviv, Israel.
Zabavnik
Natalia
N
Kopel
Rela
R
Paz-Rozner
Miri
M
Solomon
Beka
B
D000281:Administration, Intranasal; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D001923:Brain Chemistry / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003711:Demyelinating Diseases / Q000517:prevention & control; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D016056:Immunodominant Epitopes / Q000008:administration & dosage* / Q000276:immunology; D017912:Inovirus / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000737:chemistry* / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology* / Q000627:therapeutic use*
D000906:Antibodies; D016207:Cytokines; D016056:Immunodominant Epitopes; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments