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Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system. We hypothesize that angiogenesis results in new vessels which serve as a conduit for immune cell recruitment in MS, and contribute to inflammation through the pro-inflammatory properties of angiogenic regulators. This study is one of the first to explore regulation of angiogenesis in a murine model of MS (experimental autoimmune encephalomyelitis, EAE), and its potential as a therapeutic target. Angiogenesis was apparent 21 days following disease induction and correlated with clinical and pathologic scores. We documented alterations in the VEGF and Ang/Tie signaling pathways. Expression of VEGF increased at day 14 then reduced by day 21. At this time point, Ang-2 levels were elevated due to expression by infiltrating macrophages. Ang-1 was significantly reduced at day 14 and increased at day 21 due to expression by CD3+ T-cells. The same expression pattern was validated in inflammatory cells within human MS tissue. Vascular permeability increased at day 14 and returned to control levels at day 21. The volume of permeable tissue weakly correlated with angiogenesis. VEGF blockage with bevacizumab suppressed angiogenesis and reduced clinical scores and vascular permeability. Retention of CD4+ T-cells in peripheral lymph nodes and reduced T-cell proliferation was noted following treatment. Bevacizumab reduced mononuclear cell infiltration into spinal cord. Isolated CD4+ T-cells showed reduced expression of IL-17 and IFN-??. B20-4.1.1 (a monoclonal antibody against murine VEGF) reduced clinical scores and suppressed angiogenesis as did treatment with angiostatin (an inhibitor of endothelial cell proliferation). B20-4.1.1 reduced vascular permeability, induced retention of CD4+ T-cells in peripheral lymph nodes, and inhibited T-cell proliferation, while angiostatin had no effect. Isolated lymphoid cells from mice treated with both agents showed reduced secretion of IL-17, but B20-4.1.1 had no effect on Tcell proliferation or IL-17 secretion when combined with angiostatin. ?? We conclude that these angiogenesis inhibitors are effective in EAE and act by suppressing angiogenesis with a secondary effect on peripheral T-cell activation. To the extent that EAE replicates changes occurring in MS, we have demonstrated that modulation of angiogenesis may represent a promising strategy in the management of disease progression.

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Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by lesions that form within the central nervous system which induce symptoms such as muscle weakness and paralysis. Many aspects of MS, ranging from causation to immunopathology, are currently under investigation as little is known of the factors that contribute to and exacerbate this disease. Presently, evidence suggests MS to be an inflammatory disease mediated by an autoimmune response to an unknown antigen. Results from clinical studies as well as animal models such as experimental autoimmune encephalomyelitis (EAE) suggest MS is initiated and maintained by immune cells such as Th1 lymphocytes. As a result, therapeutics prescribed to MS patients’ focus on modulating the inflammatory response so as to minimize myelin loss and CNS damage. Peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors that show promise as potential targets for MS therapeutics. The PPAR sub-types, PPARα and PPARγ, have been shown to inhibit the propagation of inflammatory pathways and decrease the activity of pro-inflammatory cells in a number of inflammation driven diseases including rheumatoid arthritis and atherosclerosis. The anti-inflammatory role of PPARβ/δ is less well known, although preliminary studies suggest activation of this receptor may potentiate the activity of other transcription factors involved in inhibiting inflammatory pathways. As the PPAR family of transcription factors exhibit similar functions, it is hypothesized that the PPARβ/δ sub-type may have immunomodulatory effects that are comparable and complimentary to PPARα and –γ. This thesis describes a novel model of relapsing-remitting EAE (RR-EAE) that presents a disease course where EAE relapses are followed by periods of recovery that are characterized by the absence of clinical symptoms. Furthermore, a therapeutic intervention study carried out using this model demonstrates that the PPARγ agonist pioglitazone can decrease the severity of a relapse episode when drug treatment begins prior to a predicted relapse event. The inhibition of immune cell infiltration into the CNS and decreased immune cell activity mediated by pioglitazone, suggests that this ligand modulates the immune response. These results indicate that pioglitazone may be an effective treatment for relapsing-remitting MS. To examine the role of PPARβ/δ in RR-EAE and explore its effect on the activity of inflammatory cells, PPARβ/δ knockout mice were used due to the current lack of specific antagonists for this receptor. PPARβ/δ wild-type mice developed RR-EAE when immunized using protocol intended to induce this disease course. PPARβ/δ knockout mice however, developed chronic EAE when immunized in the same manner. Consistent with sustained clinical symptoms, CNS immune cell infiltration and activity was maintained throughout the disease in PPARβ/δ knockout mice. In contrast, the presence of immune cells within the CNS and consequent activity fluctuated according to the relapse and recovery pattern of disease in PPARβ/δ wild-type mice. PPARβ/δ appears to modulate inflammation by potentiating the apoptosis of activated T cells. Therefore, PPARβ/δ agonists may be potential candidates for MS treatment.

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Recently, several glycerophosphocholine biomarkers for multiple sclerosis were discovered in serum, plasma, and cerebrospinal fluid; little is known, however, about brain glycerophosphocholine metabolism during multiple sclerosis despite evidence that lysophosphocholines can elicit demyelination experimentally. Using a lipidomics approach, glycerophosphocholine metabolites in the hippocampus and temporal-parietal-entorhinal cortex of female C57BL/6J mice subjected to experimental autoimmune encephalomyelitis (a mouse model of multiple sclerosis) were quantified and compared to metabolite levels in healthy mice. To control for potential hormonal regulation, glycerophosphocholine metabolites from these same regions were quantified across the estrous cycle in healthy female N5 C57BL/6J x C3h/HeJ mice. I found that several critical glycerophosphocholine metabolites were significantly decreased over the course of experimental autoimmune encephalomyelitis in both brain regions, although the hippocampus was more affected compared to the temporal-parietal-entorhinal cortex. Similarly, hippocampal glycerophosphocholine metabolism was more responsive to fluctuations in female sex hormones than the cortex. Overall, these results suggest that glycerophosphocholine metabolism differs not only between brain regions, but also between conditions, namely experimental autoimmune encephalomyelitis and the estrous cycle.

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