Treatment with Soluble Tumor Necrosis Factor Receptor (sTNFR):Fc/p80 Fusion Protein Ameliorates Relapsing-remitting Experimental Autoimmune Encephalomyelitis and Decreases Chemokine Expression

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological and clinical similarities to the major human demyelinating disease multiple sclerosis (MS). Multiple lines of evidence in recent years implicate the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) in the pathogenesis of both EAE and MS. TNF-α cellular responses are mediated by signaling through receptors, which are expressed in two functional forms, designated according to molecular weight p55/60 and p75/80. We report a treatment trial using the extracellular domain of the p80 TNFR in a bivalent fusion construct designated soluble tumor necrosis factor receptor (sTNFR):Fc to treat EAE. sTNFR:Fc/p80, given after the onset of clinical signs, reduced the clinical deficit of the first attack of relapsing-remitting EAE (RR-EAE) and the exacerbation rate for subsequent attacks. The effect was reversible as mice treated with sTNFR:Fc/p80 reverted to an exacerbation rate and disease severity typical of placebo-treated animals after treatment was discontinued. Treatment of RR-EAE with sTNFR:Fc/p80 decreased expression of chemokines MIP-1α (Monocyte Inflammatory Protein)/CCL3, MIP-1β/CCL4 and MIP-2/CXCL1-2 in the central nervous system. This treatment trial reveals an important function of TNF in the pathogenesis of RR-EAE and propose the mechanism of beneficial action of sTNFR:Fc/p80 in this disease.

• Experimental autoimmune encephalomyelitis
• Multiple sclerosis
• Tumor necrosis factor receptors
• Chemokines
• Autoimmunity
• TNF, tumor necrosis factor
• TNFR, tumor necrosis factor receptor
• sTNFR:Fc, soluble recombinant TNFR:Fc fusion protein
• EAE, experimental autoimmune encephalomyelitis
• RR-EAE, relapsing-remitting experimental autoimmune encephalomyelitis
• MS, multiple sclerosis
• CSF, cerebrospinal fluid
• IL4, interleukin 4
• PI, post-immunization
• CNS, central nervous system
• MIP, monocyte inflammatory protein