Inhibition of leukotriene B4-receptor interaction suppresses eosinophil infiltration and disease pathology in a murine model of experimental allergic encephalomyelitis.
Leukotriene B4 (LTB4) is a chemotactic and cell-activating factor present at inflammatory sites in a variety of autoimmune diseases including multiple sclerosis (MS). In this study, we used a murine model of MS, experimental allergic encephalomyelitis (EAE), to assess the potential role of LTB4 on cell infiltration and paralysis. Injection of encephalogenic T cells into naive animals induced paralysis and weight loss that was completely inhibited by treatment with the selective LTB4 receptor antagonist CP-105,696 (ED50= 8.6 mg/kg orally). Although migration of lymphocytes into the central nervous system was unaffected, the efficacious effects of CP-105,696 correlated with up to a 97% decrease in eosinophil infiltration into the lower spinal cord as determined by light and electron microscopy and quantitated by levels of the specific enzyme marker eosinophil peroxidase. These results demonstrate that eosinophil recruitment in EAE is dependent on LTB4 receptor ligation and further reveal a previously unrecognized role for eosinophils in the pathogenesis of this disease.
Gladue
R P
RP
Central Research Division, Pfizer, Inc., Groton, Connecticut 06340, USA.
Carroll
L A
LA
Milici
A J
AJ
Scampoli
D N
DN
Stukenbrok
H A
HA
Pettipher
E R
ER
Salter
E D
ED
Contillo
L
L
Showell
H J
HJ
D000595:Amino Acid Sequence; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D002264:Carboxylic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D004804:Eosinophils / Q000187:drug effects*; D005260:Female; D007116:Immunization, Passive; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000276:immunology; D010243:Paralysis / Q000517:prevention & control; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D013116:Spinal Cord / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology
D001578:Benzopyrans; D002264:Carboxylic Acids; D009842:Oligopeptides; D018102:Receptors, Leukotriene B4; C089698:CP 105696