Development of a novel therapy for Lipo-oligosaccharide-induced experimental neuritis: use of peptide glycomimics.
Recent etiological studies have revealed that molecular mimicry between the lipo-oligosaccharide (LOS) component of Campylobacter jejuni and gangliosides of peripheral nervous system plays an important role in the pathogenesis of Guillain-Barré syndrome (GBS). Previously, we demonstrated GD3 ganglioside molecular mimicry in a model of GBS in Lewis rats by sensitization with GD3-like LOS (LOS(GD3)) from C. jejuni. Since the neuropathophysiological consequences were due largely to the anti-GD3-like antibodies, we subsequently focused our effort upon eliminating the pathogenic antibodies using several strategies to mimic GD3 in this model. Here, we have validated this strategy by the use of peptide glycomimics based on epitopic mimicry between carbohydrates and peptides. We treated rats by i.p. administration of phage-displayed GD3-like peptides. One GD3-like peptide (P(GD3)-4; RHAYRSMAEWGFLYS) induced in treated rats a remarkable restoration of motor nerve functions, as evidenced by improved histopathology, rotarod performance, and motor nerve conduction velocity. P(GD3)-4 effectively decreased the titer of anti-GD3/anti-LOS(GD3) antibodies and ameliorated peripheral nerve dysfunction in the sera of treated rats. The data suggest that peptide glycomimics of ganglioside may be potential powerful reagents for therapeutic intervention in GBS by neutralizing specific pathogenic anti-ganglioside antibodies.
Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912-2697, USA.
Seigo
S
Usuki
Kyoji
K
Taguchi
Yi-Hua
YH
Gu
Stuart A
SA
Thompson
Robert K
RK
Yu
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D018920:Coculture Techniques / Q000379:methods; D003429:Cross Reactions / Q000502:physiology; D004195:Disease Models, Animal; D015195:Drug Design; D005260:Female; D005732:Gangliosides / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D046529:Microscopy, Electron, Transmission / Q000379:methods; D018716:Molecular Mimicry; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D009443:Neuritis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000503:physiopathology; D009844:Oligosaccharides / Q000627:therapeutic use; D010455:Peptides / Q000627:therapeutic use*; D010525:Peripheral Nerves / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
D001323:Autoantibodies; D005732:Gangliosides; D008070:Lipopolysaccharides; D009844:Oligosaccharides; D010455:Peptides; C026226:ganglioside, GD3