A monoclonal antibody to alpha 4-integrin reverses the MR-detectable signs of experimental allergic encephalomyelitis in the guinea pig.
Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS characterized by blood-brain barrier breakdown, cerebral edema formation, lymphocyte infiltration, and demyelination, and is used as an animal model of multiple sclerosis (MS). MR imaging is important for the diagnosis of MS and for the evaluation of potential new therapies. In this study, T2-weighted and T1-weighted contrast-enhanced MR imaging was used to evaluate the effectiveness of an antiadhesion therapy in EAE. Leukocyte-endothelial adhesion at the blood-brain barrier is considered an essential step in the mediation of CNS leukocyte infiltration in EAE. AN100226m, a monoclonal antibody to alpha 4 integrin has been previously shown to reverse the clinical and histologic signs of EAE by blocking this interaction. In the present study, AN100226m treatment in acute EAE significantly decreased contrast enhancement of the CNS parenchyma indicating closure of the blood-brain barrier. The percentage of pixels due to leakage of contrast material in T1-weighted images decreased to < 4% in AN100226m-treated animals whereas it was increased to 15% in control animals (P < .05, Mann-Whitney rank sum test). A decrease in CNS abnormalities associated with cerebral edema and inflammation was also observed on T2-weighted images (P < .05, Mann-Whitney rank sum test). Thus, an antibody to alpha 4 integrin reversed the blood-brain barrier permeability changes characteristic of acute EAE. In addition, the further accumulation of inflammatory edema was prevented and preexisting edema was resolved.
Kent
S J
SJ
Department of Physiology, University Hospital, University of Western Ontario, London, Canada.
Karlik
S J
SJ
Rice
G P
GP
Horner
H C
HC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001929:Brain Edema / Q000517:prevention & control*; D015815:Cell Adhesion Molecules / Q000276:immunology* / Q000494:pharmacology; D004195:Disease Models, Animal; D017352:Echo-Planar Imaging / Q000295:instrumentation / Q000379:methods*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000175:diagnosis* / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D006168:Guinea Pigs; D007089:Image Enhancement / Q000379:methods; D039441:Integrin alpha4; D009103:Multiple Sclerosis / Q000175:diagnosis
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D039441:Integrin alpha4