Molecular mechanisms of high-dose antigen therapy in experimental autoimmune encephalomyelitis: rapid induction of Th1-type cytokines and inducible nitric oxide synthase.

Abstract

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-alpha and IFN-gamma, 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-alpha mRNA and 3-fold induction of IFN-gamma 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-gamma and iNOS mRNA remained elevated for at least 6 h, whereas TNF-alpha mRNA was already down-regulated 6 h after Ag injection. A comparable time course was found for circulating serum levels of TNF-alpha and IFN-gamma. IL-10 mRNA levels did not change significantly following Ag injection. Neutralization of TNF-alpha by anti-TNF-alpha 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-alpha 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.

• Authors: A Weishaupt, S Jander, W Brück, T Kuhlmann, M Stienekemeier, T Hartung, K V Toyka, G Stoll, R Gold
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 165 Issue 12 Pg. 7157-63 (Dec 15 2000) ISSN: 0022-1767 [Print] United States
• PMID: 11120847 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantigens
• Cytokines
• Immune Sera
• Myelin Basic Protein
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, rat

Topics

• Animals
• Apoptosis (immunology)
• Autoantigens (administration & dosage, therapeutic use)
• Cell Movement (immunology)
• Cytokines (biosynthesis, blood)
• Disease Progression
• Dose-Response Relationship, Immunologic
• Drug Administration Schedule
• Encephalomyelitis, Autoimmune, Experimental (enzymology, immunology, pathology, therapy)
• Enzyme Induction (genetics, immunology)
• Female
• Gene Expression Regulation (immunology)
• Guinea Pigs
• Immune Sera (administration & dosage)
• Injections, Intravenous
• Myelin Basic Protein (administration & dosage, immunology, therapeutic use)
• Nitric Oxide Synthase (biosynthesis, genetics)
• Nitric Oxide Synthase Type II
• RNA, Messenger (biosynthesis)
• Rats
• Rats, Inbred Lew
• Spinal Cord (enzymology, immunology, pathology)
• Th1 Cells (immunology, metabolism)
• Tumor Necrosis Factor-alpha (immunology)