Effects of intravenous immunoglobulins on T cell and oligodendrocyte apoptosis in high-dose antigen therapy in experimental autoimmune encephalomyelitis.
Intravenous immunoglobulins (IVIg) are purified preparations of immunoglobulins from plasma of healthy human donors containing polyclonal IgG and various immunomodulatory contaminants. IVIg may exert its therapeutic effect at several levels of the immune network. Antigen-specific therapy of adoptive transfer-(AT)-EAE in Lewis rats leads to elevated serum levels of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha release at sites of inflammation increased apoptosis of autoaggressive T cells in spinal cord in situ and oligodendrocyte apoptosis. In addition, autoinflammatory T cells in liver were destroyed and caused liver damage by TNF-alpha release. To explore a possible neutralizing effect of IVIg on TNF-alpha secreted by antigen-specific T cells, we analyzed T cell and oligodendrocyte apoptosis as well as liver damage in rats that had been injected with myelin basic protein (MBP) and co-treated intravenously with human IVIg. As in our earlier studies, we found that TNF-alpha serum levels were raised by antigen therapy and decreased with concomitant IVIg administration. Using IVIg treatment, antigen-induced T cell apoptosis in inflamed spinal cord and liver of MBP/IVIg-treated animals was significantly reduced compared to control rats treated with MBP/albumin. T cell apoptosis decreased to levels observed in EAE rats receiving albumin only. In addition, serum levels of liver enzymes were raised after MBP/albumin administration and decreased by co-treatment with IVIg, indicating protection of hepatocytes by the neutralization of TNF-alpha. In contrast, oligodendrocyte apoptosis in animals receiving MBP/IVIg was significantly higher than in EAE controls. This indicates that IVIg may have different tissue-specific effects. Besides neutralization of TNF-alpha-mediated cell death, IVIg may also interfere with the network of local immune cells, thus modulating survival of glial cells.
Weishaupt
Andreas
A
Department of Neurology, Neuroimmunology Branch and Clinical Research Group for Multiple Sclerosis, Julius-Maximilians Universität, Josef-Schneider-Strasse 11, 97080 Würzburg, Germany. a.weishaupt@mail.uni-wuerzburg.de
Kuhlmann
Tanja
T
Schönrock
Lisa M
LM
Toyka
Klaus V
KV
Brück
Wolfgang
W
Gold
Ralf
R
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004676:Myelin Basic Protein / Q000276:immunology; D009836:Oligodendroglia / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects*; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D016756:Immunoglobulins, Intravenous; D004676:Myelin Basic Protein; D014409:Tumor Necrosis Factor-alpha; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase