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.
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.
Weishaupt
A
A
Department of Neurology, Julius-Maximilians Universität, Würzburg, Germany.
Gold
R
R
Hartung
T
T
Gaupp
S
S
Wendel
A
A
Brück
W
W
Toyka
K V
KV
D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008107:Liver Diseases / Q000517:prevention & control; D018996:Myelin P2 Protein / Q000009:adverse effects / Q000627:therapeutic use; D009336:Necrosis; D009444:Neuritis, Autoimmune, Experimental / Q000188:drug therapy* / Q000503:physiopathology*; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*
D000941:Antigens; D018996:Myelin P2 Protein; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha