| Multiple sclerosis (MS) is a demyelinating autoimmune disease, which is characterized by infiltration and activation of T cells, and the accumulation of activated microglia and macrophages in the central nervous system. I have employed a mouse model of experimental autoimmune encephalomyelitis (EAE), to address questions related to the involvement of several factors in MS.;One of the major factors participating in the inflammation cascade of MS/EAE is nitric oxide (NO), which is produced by nitric oxide synthase (NOS). The role of NO during MS has been debated extensively. Using biochemical, cell culture, and in vivo techniques on genetically-modified mice, I identified contributions of individual NOS isoform-derived NO in the development of EAE. Specifically, I found that endothelial-NOS participates in mediating initial blood-brain barrier breakdown; neuronal-NOS contributes to excitotoxicity; and inducible-NOS is responsible for the high output of NO during EAE lesions. Furthermore, NO has been found undertaking neurodegenerative or neuroprotective functions during different phases of EAE. These results suggested that modulation of NO production from their varied cellular sources and the timing of interference may have therapeutic potential in the management of MS.;The second part of my research was to study the role of tuftsin (TKRP), a microglial activator in the modulation of T cell phenotypes and thus the progression of EAE. Previously we found that tuftsin infusion through mini-osmotic pumps abrogated disease severity in EAE mice. My further studies revealed that both in vivo and in vitro, modulating microglial activity using tuftsin switched T cell phenotype from a Th1 dominant pro-inflammatory response to a Th2 dominant anti-inflammatory response, and also favored an expansion of regulatory T cells; moreover, adoptive transfer of tuftsin modulated T cells reversed clinical symptoms in established EAE mice, indicating that the interaction between microglia and T cells could be targeted therapeutically in MS. |
