Understanding the role of white blood cell signalling in MS

Investigators

• Dr Iain Comerford, University of Adelaide
• Supervisor: Prof Shaun McColl, University of Adelaide

Funding

• $240,000 over 2010 - 2012

Summary

In MS white blood cells of the immune system enter the central nervous system (CNS) where they are thought to play a major role in driving disease and CNS degeneration.  However, CNS degeneration also occurs through non-immune mechanisms.

The work in this application will use animal models of MS and study samples of human MS tissue to investigate the role of two enzymes in controlling white blood cell activation and migration. This study has potential to lead to novel therapeutics for patients with MS, will increase understanding of activation and migration of white blood cells and determine whether these molecules regulate demyelination and remyelination of the CNS.

Progress to date

Dr Iain Comerford, working at the University of Adelaide School of Molecular and Biomedical Science, was awarded a 3 year fellowship by MSRA in 2010 to research two two enzymes that regulate immune function.

The enzymes being investigated are called ‘p110δ’ and ‘p110γ’ His research utilises laboratory models of MS to investigate the role of the two enzymes in controlling white blood cell activation and migration. These enzymes are vital for the function of a multitude of white blood cells, including T cells, B cells and neutrophils. They are therefore promising targets for drugs that prevent or treat inflammation and autoimmunity.“In multiple sclerosis (MS), white blood cells of the immune system enter the central nervous system (CNS) where they are thought to play a major role in driving disease and CNS degeneration,” reported Dr Comerford “However, CNS degeneration also occurs through non-immune mechanisms.”

In his research, Dr Comerford has used a laboratory model of experimental autoimmune encephalomyelitis (EAE) to study the important role of these enzymes in driving the central nervous system. He has published a manuscript in the Journal of Autoimmunity which presents data demonstrating that the enzyme p110δ is required for full and sustained pathology of EAE and that this enzyme is required for optimal activation of a subset of T cells which cause disease in both EAE and MS. In addition, Dr Comerford has discovered that the other enzyme, p110γ, is also required for EAE to progress and he is in the process of finalising this data for publication.

An important part of a post-doctoral fellowship, such as the award made to Dr Comerford, is to develop collaborations to enable the researcher to establish an independent career as an MS researcher in the future. To this end, Dr Comerford has been working in collaboration with A/Prof David Booth at Westmead Millennium Institute for the genetic analysis part of his project and with the MSRA Brain Bank to obtain MS tissue for his studies. He has also been supervising and mentoring two PhD students, one of whom has recently graduated; this is also a vital contribution to training the next generation of MS researcher.

The remainder of this study will now focus upon the role of these two enzymes in a non-autoimmune model of MS: the cuprizone model of CNS demyelination and remyelination. Further research is also planned to examine the role of these molecules in oligodendrocyte function and to investigate differences between these two enzymes which may exist in people with MS. “This study has potential to lead to the development of novel therapeutics for patients with MS, will increase understanding of activation and migration of white blood cells and determine whether these molecules regulate demyelination and remyelination of the CNS,” explained Dr Comerford.

Reference
Haylock-Jacobs S*, Comerford I*, Bunting M, Kara E, Townley S, Klingler-Hoffmann M,
Vanhaesebroeck B, Puri KD, McColl SR. PI3Kδ drives the pathogenesis of experimental
autoimmune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17
differentiation. J Autoimmunity. 2011 Mar 9. [Epub ahead of print]
 

Updated: 11/05/11