P091 Interferon-beta regulates Th17 and dendritic cell responses in EAE

Abstract

Introduction Multiple sclerosis (MS) is an autoimmune disease that targets the central nervous system. Interferon (IFN)- β was the first approved therapy for relapsing-remitting MS more than 10 years ago, however, its mechanism of action remains ill-defined. Methods Using a murine experimental autoimmune encephalomyelitis (EAE) model for MS, we show that mice null for IFN- β , IFN- β −/− , exhibit an earlier onset and a more rapid progression of disease compared to IFN- β +/+ mice. Results IFN- β −/− mice exhibit increased numbers of Th17 cells in their draining lymph nodes (DLN) as early as 4 days after disease induction. Th17 cells are implicated as critical effectors in different autoimmune diseases, including MS. Increased Th17 cell polarization may be driven by dendritic cells (DC), as DCs derived from IFN- β −/− mice induce greater proliferation of T cells derived from either IFN- β +/+ or IFN- β −/− mice, compared with DCs derived from IFN- β +/+ mice. In addition, adoptive transfer of myelin oligodendrocyte glycoprotein (MOG) peptide-primed IFN- β −/− DC into IFN- β +/+ and IFN- β −/− mice with EAE resulted in their rapid migration into the CNS of recipient mice, visualized by high resolution fluorescence imaging. Cytokine expression analysis revealed that DCs generated from IFN- β −/− mice secrete increased levels of IL-6, yet decreased levels of IL-27, compared with DCs generated from IFN- β +/+ mice. These data suggest that DCs from IFN- β −/− mice have a propensity to secrete cytokines perhaps associated with Th17 rather than Treg polarization. Moreover, the IFN- β −/− DCs produce lower levels of IL-1 and IL-10. The activation profiles of proteins, such as phospho-proteins that drive proliferation and activation signaling cascades, differ in disease states, both from a “normal” profile and among different pathologies. Using our mouse EAE model of MS and human MS patient peripheral blood, we are interrogating the phosphorylation status of signaling effectors, including STATs and MAPKs, by FACS-based multiparametric staining of cell surface and intracellular markers to determine the activation status of circulating discrete immune cell populations. Our staining panels allow us to discern the phosphorylation status of these signaling effectors in T cell populations and DCs. Data will be presented that describe the signature phospho-profiles during active disease/relapse and remission. Conclusion Taken together, the data indicate that IFN- β plays a role in regulating the Th17 and DC responses during EAE, by limiting cell accumulation and trafficking and by regulating cytokine production.