Fgfr1 Ablation In Oligodendrocytes Reduces Disease Severity And Inflammation In The CNS In MOG35-55 Induced EAE (P1.167)

OBJECTIVE: To study the role of the fibroblast growth factor receptor 1 (Fgfr1) in oligodendrocytes in MOG35-55 induced EAE, the animal model of multiple sclerosis. BACKGROUND: Fgfr1 is known to be expressed in the CNS by oligodendrocytes, astrocytes and microglia. Recent work suggests that the Fgfr1 is expressed by T-cells and provides costimulation for these cells. Data from EAE studies suggest that the FGF2/Fgfr1 pathway is activated in EAE. In the cuprizone model Fgfr1-/- mice showed increased remyelination. Therefore we hypothesized that the Fgfr1 in oligodendrocyte negatively regulates remyelination and the disease course of EAE possibly through altering immune cell infiltration. DESIGN/METHODS: Tamoxifen induced cre/lox-mediated deletion of Fgfr1 in oligodendrocytes was done in 4-weeks-old female mice. EAE was induced in 10 to 12-week-old mice with the MOG35-55 peptide. The clinical disease course was monitored until day 62 after EAE induction. Immune cell infiltrates (T-cells, B-cells and macrophages) were quantitatively analyzed by immunostaining, proinflammatory cytokines were analyzed by RT PCR. RESULTS: Conditional deletion of the Fgfr1 in oligodendrocytes resulted in a milder course of EAE in the chronic phase (day 62, p = 0.003). Proteolipid protein expression was not affected in Fgfr1-/- mice. T-cell (p = 0.001), B-cell (p = 0.005) and macrophage (p = 0.049) infiltrates were significantly reduced in spinal cord white matter lesions of Fgfr1-/- mice. There were no differences in proinflammatory cytokine mRNA levels (IL1β, IL6, IL12, iNOS and TNFα) in the spinal cord between control and FGFR1-/- mice. CONCLUSIONS: Our results suggest that the Fgfr1 in oligodendrocytes negatively influences the disease course of chronic EAE. The underlying mechanism could be that the Fgfr1 blockade results in reduced costimulation of T-cells as well as other inflammatory cells in the CNS. Since cytokine expression is not changed, other mechanisms such as neuronal growth factors or alternative cell proliferation pathways may explain the reduced inflammation. Study Supported by: This study was supported by MERCK Serono. Disclosure: Dr. Rajendran has nothing to disclose. Dr. Giraldo Velasquez has nothing to disclose. Dr. Stadelmann-Nessler has received personal compensation for activities with Teva Neuroscience. Dr. Berghoff has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Merck & Co. Inc., Teva Neuroscience, Biogen Idec, and Novartis. Dr. Berghoff has received research support from Bayer Pharmaceuticals Corporation, Teva Neuroscience, Merck & Co. Inc., Biogen Idec and Novartis.