Date of Award

1-1-2012

Document Type

Campus Access Dissertation

Department

Biomedical Science

First Advisor

Mitzi Nagarkatti

Second Advisor

Prakash S Nagarkatti

Abstract

Multiple Sclerosis (MS) is a neurodegenerative autoimmune disease that affects about 400,000 people in the US and close to 2 million people worldwide. Although the direct cause of this disease remains unknown, it has been demonstrated that CD4+ T-cell subsets Th1 and Th17, play a significant role in driving disease progression. Current treatment consists of anti-inflammatory or immunosuppressive drugs in an attempt to suppress the production of pro-inflammatory cytokines as well as the activation, expansion, and migration of autoreactive T-cells. However, treatments options have been shown to only be effective to 20 - 30% of MS patients and may result in adverse effects. The current study investigates the effects and mechanisms of two alternative methods of treatment that may provide a safer and more effective way to alleviate the symptoms of MS. In a mouse model of MS, known as experimental autoimmune encephalomyelitis (EAE), we demonstrate that pre-treatment with recombinant interleukin-2 (rIL-2) upregulates the frequency of immunosuppressive regulatory T-cells (T-regs), which leads to the suppression of Th17 differentiation and cellular infiltration into the central nervous system (CNS) of diseased mice. As a result, EAE mice pre-treated with rIL-2 displayed a significant reduction in the severity of clinical symptoms. In addition, we were able to show for the first time that dietary indoles, indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) can dramatically inhibit the development of EAE as demonstrated by reduced clinical scores and maintenance of architecture of spinal cord histopathology. These dietary indoles exhibited their immunomodulatory effects through interaction with the aryl hydrocarbon receptor (AhR) as well as the estrogen receptor (ER). Furthermore, I3C and DIM treatment in EAE mice led to altered miRNA expression in CD4+ T-cells, which may play a pivotal role in regulating T-cell activation and expansion. Our studies using EAE as a model illustrate two novel treatment modalities that can be used as safer and more efficient options to potentially alleviate the development and progression of MS.

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