Inhibition of tumor necrosis factor is protective against neurologic dysfunction after active immunization of Lewis rats with myelin basic protein.
Increasing evidence indicates that the cytokines, tumor necrosis factor (TNF), interleukin-1, and/or interferon-gamma, may play a crucial role in the pathogenesis of multiple sclerosis. Several reports demonstrated that inhibition of TNF is highly protective in experimental allergic encephalomyelitis (EAE) when sensitization is accomplished by the passive transfer of myelin basic protein (MBP) sensitized lymphocytes. However, successful protection has not been reported in EAE that is induced by active immunization with MBP. We examined the effects of a TNF inhibitor, dimeric polyethylene glycol linked form of the type I soluble receptor of TNF, PEG-(rsTNF-RI)2, on actively acquired EAE. Treatment with PEG-(rsTNF-RI)2 at 0.3-3 mg/kg every other day or every third day starting on Day 9 postimmunization with MBP during the effector phase of EAE significantly inhibited clinical signs in a dose-dependent manner. Histological examination of the central nervous system indicated that the administration of PEG-(rsTNF-RI)2 reduced, in part, the cellular infiltrate, particularly in the lumbar and sacral regions of the spinal cord. These studies suggest that TNF is a pivotal mediator of the inflammation resulting from the complete immune response induced by active immunization with MBP.
Martin
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Department of Pharmacology, Synergen Inc., Boulder, Colorado 80301, USA.
Near
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Bendele
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Russell
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DA
D000818:Animals; D002490:Central Nervous System / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D004306:Dose-Response Relationship, Immunologic; D004334:Drug Administration Schedule; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005620:Freund's Adjuvant; D007114:Immunization / Q000379:methods; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology* / Q000633:toxicity; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012720:Severity of Illness Index; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology; D015431:Weight Loss
D004676:Myelin Basic Protein; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D011092:Polyethylene Glycols; D016572:Cyclosporine; D005620:Freund's Adjuvant