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A Novel Model of Demyelinating Encephalomyelitis Induced by Monocytes and Dendritic Cells¹

Glaucia C. Furtado^2,*, Beatrice Piña^*, Frank Tacke^3,, Stefanie Gaupp, Nico van Rooijen^¶, Thomas M. Moran, Gwendalyn J. Randolph, Richard M. Ransohoff^#, Stephen W. Chensue^||, Cedric S. Raine and Sergio A. Lira^*

^* Immunobiology Center, Department of Gene and Cell Medicine, Department of Microbiolology, Mount Sinai School of Medicine, New York, NY 10029; Department of Pathology (Neuropathology), Albert Einstein College of Medicine, New York, NY 10461; ^¶ Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, The Netherlands; ^|| Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195; and ^# University of Michigan Medical School, Ann Arbor, MI 48105

Local inflammation may be a precipitating event in autoimmune processes. In this study, we demonstrate that regulated influx of monocytes and dendritic cells (DC) into the CNS causes an acute neurological syndrome that results in a demyelinating encephalomyelitis. Expansion of monocytes and DC by conditional expression of Flt3 ligand in animals expressing CCL2 in the CNS promoted parenchymal cell infiltration and ascending paralysis in 100% of the mice within 9 days of Flt3 ligand induction. Depletion of circulating monocytes and DC reduced disease incidence and severity. Unlike the classical models of experimental autoimmune encephalomyelitis, depletion of CD4⁺ and CD8⁺ T cells did not affect disease induction. T cells and demyelinating lesions were observed in the CNS at a later stage as a result of organ-specific inflammation. We propose that alterations in the numbers or function of monocytes and DC coupled to dysregulated expression of chemokines in the neural tissues, favors development of CNS autoimmune disease.

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 National Multiple Sclerosis Society Grants (G 3479-A-2 (to G.C.F.) and RG 1001-k-11 (to C.S.R.), the Irene Diamond Fund (to S.A.L.), and National Institutes of Health Grants DK 067989 (to S.A.L.), and NS 11920 and NS 08952 (to C.S.R.).

² Address correspondence to Dr. Glaucia C. Furtado, Immunobiology Center, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1630, New York, NY 10029-6574. E-mail address: glaucia.furtado{at}mssm.edu

³ Current address: University Hospital Aachen, Medical Clinic III, Aachen, Germany.

⁴ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; DC, dendritic cell; MBP, myelin basic protein; Flt3L, Fms-like tyrosine kinase 3 ligand; DOX, doxycycline; TB, toluidine blue; MS, multiple sclerosis; EM, electron microscopy.

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