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Dr. André Müeller gave a platform presentation titled “MS Disease Activity Inhibits Hepatocyte Growth Factor (HGF) Production Within the CNS – A New Putative Mechanism Contributing to Lack of Lesion Repair Seen in MS”at the 2011 meeting of the Society for Neuroscience in Washington DC. The cytokine Hepatocyte Growth Factor (HGF) is known to possess neuroprotective and anti-inflammatory properties, to enhance axonal outgrowth, and to promote oligodendrocyte maturation. Dr. Mueller showed significant reductions in HGF expression in the cerebrospinal fluid (CSF) of MS patients versus healthy adults without differentiation by MS subtype but with greater reductions in CSF HGF in patients with active disease than those with inactive disease. The mechanism by which MS disease affects CSF HGF appears to be its regulation of cytokines and chemokines affecting HGF expression; specifically, increases in IFN-γ, IL1-β, and TGF-β inhibit HGF production while CSF levels of CCL2 strongly correlate with CSF HGF. These findings suggest that reductions in CSF HGF may contribute to the imperfect repair of demyelination associated with MS, and present HGF-regulating cytokines and chemokines in CSF as potentially useful biomarkers of MS disease.
*The abstract can be found under Abstracts
Dr. Müeller offered summaries of eleven papers presented at the 2011 SFN Meeting. These were:
· “Intravenous administration of human multipotent adult progenitor cells provides functional benefit through immunomodulation in a mouse model of multiple sclerosis,” by Bausch et al. The authors report that IV administration of adult progenitor cells decreases the severity of CNS symptoms in a mouse model (EAE) of MS, with the finding that adult human stem cells can modulate autoimmune disorders.
· “MSCs ameliorate clinical course in rats with experimental autoimmune encephalomyelitis,” by Scuteri et al. Mesenchymal stem cells (MSCs) from rats were shown to reduce the severity of CNS symptoms in EAE, and to reduce expression of autoimmune cytokines in the spinal cord.
· “Expression of sonic hedgehog targeted genes in peripheral blood mononuclear cells of patients with Multiple Sclerosis,” by Kaminska-Czajkowska et al. Cells expressing the Olig1 and Olig2 genes were found to be higher in the peripheral blood of (RR)MS patients than in healthy controls.
· “Reduction of cd133 positive stem cells circulating in the peripheral blood of patients with relapsing remitting multiple sclerosis,” by Finkelsztein et al. It was found that RRMS patients have reduced numbers of cd133 positive stem cells in their peripheral blood in comparison to healthy controls, but no difference in the functional character of the cd133+ cells of EAE mice and those of control animals was detected.
· “Ephrin B3 negatively regulates oligodendrocyte maturation and CNS remyelination,” by Syed et al. As it is known that myelin inhibits the differentiation of oligodendrocyte progenitor cells, (OPCs), the authors determined that among myelin components, Ephrin B3 inhibits OPC maturation both in vitro and in vivo; further, it was found that EB3 is present in demyelinated lesions and that EB3 antibodies promote remyelination.
· “Biochemical and immunological characterization of activated astrocytes,” by Algeciras et al. The authors report that myelin components are able to activate astrocytes, and that increased expression of CD80, CD86, CD137 and CD137L cytokines was detected in activated astrocytes.
· “Development of a novel method to purify and culture rodent astrocytes,” by Foo et al. Neonatal astrocytic cell cultures differ from adult astrocytes in terms of gene expression profiles, proliferation patterns, and reliance on non-CNS serum proteins, limiting the utility of such cultures for experimentation in adult MS/demyelination disorders; the authors report a technique for isolating astrocytes from adult animals that addresses these concerns.
· “Role of CREB and CRTC1 in the regulation of dendritic development by HGF,” by Finsterwald and Martin. Hepatocyte growth factor (HGF) supports CNS recovery by increasing dendritic length and branching; the authors report the mediating role of CREB and CRTC1 in promoting HGF activity, and the increased effectiveness of HGF when co-administered in vivo with brain-derived neurotrophic factor (BDNF).
· “Inhibition of soluble TNF is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination,” by Brambilla et al. Tumor necrosis factor (TNF) exists in two biologically active forms, a soluble form binding TNF receptor 1 and a transmembrane form binding both TNFR1 and TNFR2. While non-selective inhibition of both forms provides no protection against the clinical course of EAE, selective inhibition of TNFR1 through a soluble TNF blocker improves outcomes in experimental animals.
· “Defects in homocysteine metabolism play a role in the pathogenesis of multiple sclerosis ,” by Groover et al. The authors report statistically significant differences in metabolism homocysteine, which interconverts into methionine and cysteine, between progressive MS patients on one hand and RRMS patients and controls on the other hand. Administration of methotrexate, which is one of few effective treatments for progressive MS, correlated with increased plasma homocysteine, while administration of folate, to which methotrexate is antagonistic, correlated with a reduction in homocysteine.
· “Members of the TAM receptor tyrosine kinases and their ligands are implicated in the susceptibility to Multiple Sclerosis and are upregulated in the peripheral blood of those with recent onset disease,” by Kilpatrick et al. The signaling of TAM family of receptor tyrosine kinases (Tyro3, Axl, and MerTK) and their ligands Gas-6 and Protein S, were shown to correspond to immune response to the early onset of demyelinating disease, during which they were significantly upregulated, as well as and cell survival and proliferation. The MerTK gene presents a novel risk for MS susceptibility and in general the TAM family and its ligands may serve as important biomarkers of disease activity.