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.
| Identifer | oai:union.ndltd.org:ADTP/253987 |
| Creators | Madusha Peiris |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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