The Division of Clinical Neurology's main interest is multiple sclerosis (MS). We investigated paradoxically shared signalling pathways for interferon type 1 (IFN), an MS treatment, and interleukin-12 (IL-12), a proinflammatory cytokine detrimental in MS. We showed that different factors modulate the pathway differently when activated by IFN and IL-12, and that MS patients have an intrinsic IFN signalling deficit. We showed that astrocytes can express and produce most elements of the IL-12 family of cytokines.
We have shown induction of regulatory T (Treg) cells that protect against autoimmunity, by steroids, and induction of the main transcription factor for Treg cells, foxp3, by steroids and IFN. We investigate how IL-12 suppresses signalling pathways essential for Treg function.
We also investigate the role of T cells producing IL-17 (Th17) cells in MS. We have identified a Th17 marker.
Another line of investigation relates to the role of the innate immune system (comprising dendritic cells and other antigen presenting cells) in regulating inflammatory demyelination in the central nervous system (CNS). Specifically we are focusing on the role of Toll-like receptors (TLRs) in modulating the function of Tregs and other classes of immune cells in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Studies in EAE will be essential for preclinical testing of new treatments for MS and to address mechanisms of CNS inflammation, demyelination, and neuronal damage in vivo.
On the imaging side, we have applied advanced MRI (diffusion tensor imaging, magnetisation transfer imaging, T1 mapping) to quantifying MS pathology. We developed an accurate method of measuring spinal cord area.
In the next 1-2 years we will continue studies to determine whether immunotherapy normalises the MS IFN signalling deficit. Detailed studies of Th17 cells and the novel marker we identified are planned. Treg and Th17 regulation by cytokines, vaccines, and parasites will be studied. We plan an immunomodulation trial of hookworms in MS. We will validate several novel MS targets in experimental models. We will embark soon in a high field (3T and 7T) MRI study of MS, where some of the subjects will be investigated serially.
Facilities: cell and molecular biology, tissue culture, PCR, image analysis software, access to flow cytometry and real time PCR.