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* Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201;
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226; and
Laboratory of Immunology, Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
Multiple sclerosis (MS) is a CNS autoimmune disease believed to be triggered by T cells secreting Th1-specific proinflammatory cytokines, such as GM-CSF. In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), Th1 but not Th2 cells have been shown to induce disease; however, to date, no single encephalitogenic T cell-derived cytokine has been shown to be required for EAE onset. Because GM-CSF-deficient mice have been shown to be resistant to EAE following immunization with myelin self-Ag, we investigated the cellular source of the required GM-CSF and found that GM-CSF production by encephalitogenic T cells, but not CNS resident or other peripheral cells, was required for EAE induction. Furthermore, we showed that microglial cell activation, but not peripheral macrophage activation, was a GM-CSF-dependent process. Activation of microglial cells by the injection of LPS abrogated the GM-CSF requirement for EAE induction, suggesting that microglial cell activation is required for EAE onset. These data also demonstrate that GM-CSF is a critical Th1 cell-derived cytokine required for the initiation of CNS inflammation associated with EAE, and likely MS.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Research Grant RO1 NS46662-01A1 and the BloodCenter of the Wisconsin Research Foundation.
2 Address correspondence and reprint requests to Dr. Bonnie N. Dittel, Blood Research Institute, BloodCenter of Wisconsin, P.O. Box 2178, Milwaukee, WI 53201-2178. E-mail address: bonnie.dittel{at}bcw.edu
3 Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; i.c., intracranially; MBP, myelin basic protein; BM, bone marrow; ODN, oligodeoxynucleotide; WT, wild type; HPRT, hypoxanthine phosphoribosyltransferase.
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