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*
Department of Neurology, Neuroimmunology Branch and Clinical Research Group for Multiple Sclerosis, Julius-Maximilians Universität, Würzburg, Germany;
Department of Neurology, Heinrich-Heine-Universität, Düsseldorf, Germany;
Department of Neuropathology, University of Berlin, Charite Campus Virchow, Berlin, Germany; and
§
Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Konstanz, Germany
High-dose Ag administration induces apoptotic death of autoreactive
T cells and is an effective therapy of experimental autoimmune diseases
of the nervous system. To explore the role of cytokines in Ag-specific
immunotherapy, we analyzed mRNA induction and protein expression for
the proinflammatory cytokines TNF-
and IFN-
, the
anti-inflammatory cytokine IL-10, and the cytokine-inducible NO
synthase (iNOS) during high-dose Ag therapy of adoptive transfer
experimental autoimmune encephalomyelitis (AT-EAE) in the Lewis rat.
Using semiquantitative and competitive RT-PCR, we found 5- to 6-fold
induction of TNF- mRNA and 3-fold induction of IFN- mRNA in the
spinal cord that occurred within 1 h after i.v. injection of Ag
and was accompanied by a 2-fold increase of iNOS mRNA. Both IFN- and
iNOS mRNA remained elevated for at least 6 h, whereas TNF- mRNA
was already down-regulated 6 h after Ag injection. A comparable
time course was found for circulating serum levels of TNF- and
IFN-. IL-10 mRNA levels did not change significantly following Ag
injection. Neutralization of TNF- by anti-TNF- antiserum in
vivo led to a significant decrease in the rate of T cell and
oligodendrocyte apoptosis induced by high-dose Ag administration, but
did not change the beneficial clinical effect of Ag therapy. Our data
suggest profound activation of proinflammatory but not of
anti-inflammatory cytokine gene expression by high-dose Ag
injection. Functionally, TNF- contributes to increased apoptosis of
both autoaggressive T cells and oligodendrocytes in the target organ
and may thereby play a dual role in this model of Ag-specific therapy
of CNS autoimmune diseases.
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