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Signal Transduction Inhibition of APCs Diminishes Th17 and Th1 Responses in Experimental Autoimmune Encephalomyelitis¹

Mario Skarica^*, Tianhong Wang^*, Erin McCadden^*, David Kardian^*, Peter A. Calabresi, Donald Small^*, and Katharine A. Whartenby^2,*

^* Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, and Department of Neurology and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore MD 21231

IL-17- and IFN--secreting T cells play an important role in autoimmune responses in multiple sclerosis and the model system experimental autoimmune encephalomyelitis (EAE). Dendritic cells (DCs) in the periphery and microglia in the CNS are responsible for cytokine polarization and expansion of this T cell subset. Our results indicate that in vivo administration of a signal transduction inhibitor that targets DCs to mice with EAE led to a decrease in CNS infiltration of pathogenic Ag-specific T cells. Since this approach does not target T cells directly, we assessed the effects on the APCs that are involved in generating the T cell responses. Since in EAE and multiple sclerosis, both microglia and peripheral DCs are likely to contribute to disease, we utilized a bone marrow chimera system to distinguish between these two populations. These studies show that peripheral DCs are the primary target but that microglia are also modestly affected by CEP-701, as numbers and activation states of the cells in the CNS are decreased after therapy. Our results also showed a decrease in secretion of TNF-, IL-6, and IL-23 by DCs as well as a decrease in expression of costimulatory molecules. We further determined that levels of phospho-Stat1, Stat3, Stat5, and NF-B, which are signaling molecules that have been implicated in these pathways, were decreased. Thus, use of this class of signal transduction inhibitors may represent a novel method to treat autoimmunity by dampening the autoreactive polarizing condition driven by DCs.

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 Cancer Institute Grant RO1-CA11989 (to K.A.W.), National Institutes of Health Grant NS041435 and National Multiple Sclerosis Society Grant TR-3760-A3 (to P.A.C.), and National Cancer Institute Grant RO1-CA70970 and the Kyle Haydock Professorship (to D.S.).

² Address correspondence and reprint requests to Dr. Katharine A. Whartenby, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Bunting-Blaustein Cancer Research Building, Room 2M46, 1650 Orleans Street, Baltimore, MD 21231. E-mail address: whartenby{at}jhmi.edu

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived dendritic cell; EAE, experimental autoimmune encephalomyelitis; FL, FLT3 ligand; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis.