Role of TNF-alpha in high-dose antigen therapy in experimental autoimmune neuritis: inhibition of TNF-alpha by neutralizing antibodies reduces T-cell apoptosis and prevents liver necrosis.

Abstract

TNF-alpha has been implicated as a potentially detrimental cytokine in autoimmune disorders of the nervous system and has been reported to be elevated in antigen-specific therapy of experimental autoimmune neuritis (EAN) in vivo. To investigate the role of TNF-alpha in EAN in rats that had been subjected to antigen-specific therapy with human P2 protein, animals were cotreated with an anti-TNF-alpha neutralizing antibody and the effects of the antibody on disease determined. Using this strategy in adoptive transfer (AT-) EAN, antigen-induced T-cell apoptosis in inflamed sciatic nerve and in liver was reduced to levels observed in control animals indicating that TNF-alpha mediates antigen-induced apoptosis of inflammatory T-cells. Focal liver necrosis, which had been observed in earlier studies after antigen therapy in AT-EAN, was prevented by passive immunization with neutralizing anti-TNF-alpha antibody. Unexpectedly, neutralization of TNF-alpha only partly abolished the protective effect of antigen therapy on the overall disease course. This may indicate that inhibition of TNF-alpha exerts beneficial effects other than through T-cell apoptosis, or that some of the benefit of antigen therapy is mediated by other pathways. These results indicate that secretion of TNF-alpha during antigen therapy has the dual potential to mediate beneficial apoptosis of inflammatory T-cells in the inflammatory lesion and to induce liver damage as a severe side effect.

• Authors: A Weishaupt, R Gold, T Hartung, S Gaupp, A Wendel, W Brück, K V Toyka
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 59 Issue 5 Pg. 368-76 (May 2000) ISSN: 0022-3069 [Print] England
• PMID: 10888366 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens
• Myelin P2 Protein
• Recombinant Proteins
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Antigens (administration & dosage, adverse effects, therapeutic use)
• Apoptosis (drug effects)
• Cell Line
• Chemical and Drug Induced Liver Injury
• Dose-Response Relationship, Drug
• Female
• Humans
• Liver (pathology, physiopathology)
• Liver Diseases (prevention & control)
• Myelin P2 Protein (adverse effects, therapeutic use)
• Necrosis
• Neuritis, Autoimmune, Experimental (drug therapy, physiopathology)
• Rats
• Rats, Inbred Lew
• Recombinant Proteins (adverse effects, therapeutic use)
• Sciatic Nerve (pathology, physiopathology)
• T-Lymphocytes (metabolism, physiology)
• Tumor Necrosis Factor-alpha (adverse effects, antagonists & inhibitors, immunology, physiology)