Focal experimental autoimmune encephalomyelitis in the Lewis rat induced by immunization with myelin oligodendrocyte glycoprotein and intraspinal injection of vascular endothelial growth factor.
Various models of experimental autoimmune encephalomyelitis (EAE) have led to insights into the pathogenesis and novel therapies for multiple sclerosis. One generalized EAE model uses immunizing the Lewis Rat with myelin oligodendrocyte glycoprotein (MOG) and complete Freund's adjuvant that induces systemic disease and inflammatory lesions at random central nervous system (CNS) locations. These lesions result from a combination of sensitized T cells and pathogenic antibodies gaining access to the CNS to cause an immune assault on myelin-expressing oligodendrocytes. We report a focal and temporal variant of the EAE model that results in immune-mediated demyelination at a predictable time and location. Lewis rats were immunized with the extracellular domain (1-125) of recombinant rat MOG in incomplete Freund's adjuvant (IFA) to induce a clinically silent humoral response. Vascular endothelial growth factor (VEGF) was then microinjected into the spinal cord to induce a transient, focal breakdown of the blood brain barrier (BBB). Clinical signs were apparent within 72 hours and began to resolve by day 21. The histopathology at the site of injection consisted of a focal region containing OX-42(+) cells, phagocytic cells with debris, extensive demyelination, and some lymphocyte infiltration. Neither intraspinal injection of PBS into immunized animals nor VEGF into animals treated with IFA alone resulted in clinical lesions. Thus, a transient, focal opening of the BBB with VEGF in animals with subclinical MOG immunization leads to a discrete inflammatory demyelinating lesion. This model may be useful for the study of transplanted myelin-forming cells in a discrete inflammatory demyelinating lesion.
Sasaki
Masanori
M
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06516, USA.
Lankford
Karen L
KL
Brown
Robert J
RJ
Ruddle
Nancy H
NH
Kocsis
Jeffery D
JD
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D017252:CD3 Complex / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005620:Freund's Adjuvant / Q000009:adverse effects; D007278:Injections, Spinal / Q000379:methods; D008055:Lipids / Q000009:adverse effects; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000009:adverse effects*
D000906:Antibodies; D017252:CD3 Complex; D008055:Lipids; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D042461:Vascular Endothelial Growth Factor A; C114843:incomplete Freund's adjuvant; D005620:Freund's Adjuvant