Multiple Sclerosis Group Current Research

Project One: Targeting Immune Suppressor Cells to Fight Multiple Sclerosis 

Previously we have shown that a modified superantigen (mSag) coupled to a myelin-derived peptide (MOG) alleviates the symptoms of disease in experimental autoimmune encephalomyelitis (EAE), a well-established murine model of MS. The mechanism of protection is unknown but we have proposed that it involves the expansion and/or activation of a population of MOG specific T regulatory cells (Tregs).

Tregs are a specialised immune cell type that suppress immune responses and therefore play a crucial role in preventing autoimmune disease. It has been shown that Tregs from the peripheral blood of MS patients have impaired suppressive function compared with healthy donors and it is thought that MS results from an inability of these cells to adequately turn off disease-causing self-reactive T cells. One of the goals of our research is to develop an immunotherapeutic agent that can be used to restore the suppressive function of Tregs in patients with MS.

It is known that antigen presenting cells (APCs) are important for Tregs to acquire their suppressive function. In 2007 we investigated the interactions between Tregs and APCs during immune suppression.

By labelling the mSag-peptide conjugate with a fluorescent dye, we were able to show that it bound to a distinct subpopulation of cells in the blood. The presence of MHC class II molecules was not necessary for binding of the mSag to this distinct newly identified cell subset, suggesting the presence of a second receptor for mSag binding to APCs. We also demonstrated that binding of control mSag-MOG to the blood-borne cells ameliorated symptoms and delayed the onset of disease in our EAE model.

We hypothesise that the mSag binds to and changes certain properties of the specific blood-borne cells identified in this study. Such changes endow these cells with the ability to suppress EAE.

Identification of the underlying mechanisms involved in this process is crucial for the development of an immunotherapy that can be used to treat and prevent MS and other autoimmune diseases. We are therefore very pleased to welcome Dr Elizabeth Forbes to our team, who brings with her the expertise required to study the cellular and molecular mechanisms involved in the mSag-peptide conjugate inhibition of autoimmunity.

Project Two: Understanding the Signalling Pathways involved in Multiple Sclerosis

Th1 cells producing cytokines are considered the predominant disease-causing cells in autoimmune disorders. However, the recent identification of a novel subset of autoimmune IL-17 producing CD4+ T cells (Th17 cells) suggests other cells and signaling pathways may also play a critical role in inducing autoimmunity.

A key player in the IL-17 signaling pathway is Tyk2, an intracellular kinase that has previously been shown to be necessary for the generation of autoimmune arthritis. In 2007 we demonstrated that mice that are unable to produce the Tyk2 protein are resistant to the development of EAE. Although these mice did not develop disease, they did produce normal levels of IL-17. Our results indicate that signaling via Tyk2 is important in the induction phase of EAE and the generation of disease-causing autoimmune Th17 cells.

This is the first time a link has been demonstrated between Tyk2, IL-17 and EAE. We are currently investigating other pathways involving Tyk2 to determine its potential applicability as a drug target for the treatment of autoimmune disorders such as MS.

Clinical Relevance and Future Direction

Our immediate goal is to continue to use cell-based approaches to enhance the efficiency and number of Treg cells elicited by the modified superantigen-peptide conjugate.

For this to be possible we need to identify the molecules, cytokines and cell types involved in this response.  This information will help guide in the preclinical development of the modified superantigen-peptide conjugate into a novel therapeutic agent for treating MS.  If successful, this technology could also be applied to other autoimmune diseases such as diabetes and arthritis. 

Collaborators

Prof Claude Bernard, Monash University, Melbourne, Australia
Prof John Fraser, Auckland University, New Zealand
Dr Ian van Driel, University of Melbourne, Australia