Glatiramer Acetate Treatment Regulates CD44, Receptor For Osteopontin In EAE Mice (P1.214)

Background: Multiple sclerosis (MS) starts with increased migration of autoreactive lymphocytes across the blood-brain barrier. Transfer of glatiramer acetate (GA) conditioned B cells leads to increased production of immunoregulatory cytokines/chemokines and reduced CNS inflammation in EAE disease (Begum-Haque, 2011). There is evidence that CD44+ cell and its ligand osteopontin (OPN) can play a critical role in the regulation of MS/EAE. The deletion of CD44+ cells was shown to mediate a Th2-biased immune response in MS/EAE. Recently, others and we have linked OPN expression by DCs to the production of IL-17 and have demonstrated that Th1-Th2-Th17 cytokines balance affects the MS disease progress or recovery (Steinman, L. 2007; Begum-Haque, 2011). Objective: To investigate OPN and its’ receptor expression in cell from GA treated EAE mice. Methods and Results: Tissues from immune organs were collected from GA treated and untreated EAE 2D2TCRTg mice. OPN expression and the proinflammatory/Anti inflammatory cytokines/chemokines were determined by RT-PCR in lymphocytes and DCs following in vitro MOG stimulation. GA suppresses OPN expression in DCs and B cells, coincident with the down-regulation of RORγt and IFNγ expression. In transmigration assays, stained CD19+CD44+ cells were added to the top compartment and brain cells with rOPN added to the bottom. Migrated cells were counted by FACS. The migration of cells from GA treated mice was significantly reduced compared with cells from untreated EAE mice. Conclusions/Relevance: Our studies indicate that CD44 and its ligand OPN plays a crucial role in the regulation of neuroinflammation during EAE/MS. GA treatment downregulate OPN expression and CD44+ cell in EAE mice with an associated decrease in IL-17 expression and a concomitant rise in the regulatory cytokines IL-10 and IL-13 expression within the CNS. These findings further support the potential therapeutic effect of GA in controlling CNS demyelination. Further mechanistic evidence is needed for the effect of GA on the role of CD44 in ensuing pathogenesis. Supported by Teva Neuroscience Disclosure: Dr. Begum-Haque has received research support from Teva Pharmaceuticals. Dr. Christy has nothing to disclose. Dr. Telesford has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Kasper has nothing to disclose. Dr. Haque has nothing to disclose. Dr. Kasper has received personal compensation for activities with Teva Neuroscience, EMD Serono, Bayer Pharmaceuticals Corp., Genentech Inc., and Mederex as a consultant and scientific advisory board member. Dr. Kasper has received research support from Teva Neuroscience, EMD Serono, and Bayer Pharmaceuticals Corp.