Multiple Sclerosis Group

Group Leader
Professor Trevor Kilpatrick, MBBS (Melb) PhD (Melb) FRACP

Research Fellows
Dr Helmut Butzkueven, MBBS (Melb) PhD (Melb) FRACP
Dr Holly Cate, BSc (Univ Nth Carolina), MSc (Univ Nth Carolina), PhD (Georgia State Univ)
Dr Tobias Merson, BA, BSc (Hons) PhD (Melb)
Dr Simon Murray, BSc (Hons) (Melb), BAppSci (Physiotherapy) (LaTrobe) PhD (Mon)
Dr Junhua Xiao, MB BS (Nanjing Med. Uni), PhD (Melb)

Research Assistants
Ms Michele Binder, BSc (Hons) (Syd), MSc (Melb)
Mr Dennis Kemper
Mr Bill Doherty
Mr Daniel Merlo
Ms Pik Ying Soo, BSc (Mon)

Graduate Students
Ms Vilija Jokubaitis, BCom/BSc (Hons) (Melb) (PhD student)
Ms Anna Jonas (PhD student)
Mr Gerry Ma (Honours student)
Ms Laura Oluich (PhD student)
Ms Jennifer Sabo (PhD student)
Ms Agnes Wong (PhD student)
Ms Melanie Willingham (PhD student)

The Multiple Sclerosis Group is focused on developing strategies to limit the severity of demyelinating diseases of the central nervous system, of which MS is the most common cause. Multiple sclerosis is thought to result from an autoimmune attack against myelin, which is produced by specialised glial cells known as oligodendrocytes that ensheath neurons. Whilst currently available therapies have some capacity to reduce disease activity via immunomodulatory mechanisms there are, as yet, no established treatments that either reduce oligodendrocytic damage or enhance nervous system repair, strategies that our laboratory is focusing upon.

In order to achieve these goals, we recognise the need to utilise state of the art technologies in molecular and cellular neurobiology, as well as to study whole animal models of demyelinating disease. We utilise genetically modified animals that express marker genes expressed by oligodendrocyte specific promoters in order to quantify oligodendrocytic rescue. We also generate conditional knockout mice in which key genes are selectively deleted from oligodendrocytes, in order to interrogate their influence upon these cells, both in health and in disease. Access to these technologies places us at the vanguard of basic laboratory research into demyelinating diseases.

Our previous work has established that the cytokine, leukemia inhibitory factor (LIF), enhances the viability of oligodendrocytes after a demyelinating insult and indicates that LIF receptor signaling is an important component of the endogenous oligodendroglial response to environmental stressors. Recent work has concentrated upon the actions of modulators of the LIF response, in particular the suppressors of cytokine signaling (SOCS). In particular, we have established that SOCS3 is a negative regulator of LIF signaling in oligodendrocytes, suggesting that the inhibition of SOCS activity within these cells might enhance the therapeutic utility of LIF. We are also investigating how other signaling molecules might either enhance oligodendrocytic viability or potentiate the capacity of precursor cells to differentiate into oligodendrocytes.

Publications

1. Xiao J, Wong AW, Willingham MM, Kaasinen SK, Hendry IA, Howitt J, Putz U, Barrett GL, Kilpatrick TJ, Murray SS. BDNF exerts contrasting effects on peripheral myelination of NGF-dependent and BDNF-dependent DRG neurons. J Neurosci. 2009 29(13):4016-22.
   
2. Rubio JP, Stankovich J, Field J, Tubridy N, Marriott M, Chapman C, Bahlo M, Perera D, Johnson LJ, Tait BD, Varney MD, Speed TP, Taylor BV, Foote SJ, Butzkueven H, Kilpatrick TJ. Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians. Genes Immun. 2008; 9(7):624-30.
3. Butzkueven H, Kolbe SC, Jolley DJ, Brown JY, Cook MJ, van der Mei IA, Groom PS, Carey J, Eckholdt J, Rubio JP, Taylor BV, Mitchell PJ, Egan GF, KILPATRICK TJ. Validation of linear cerebral atrophy markers in multiple sclerosis. J Clin Neurosci. 2008 Feb;15(2):130-7.
4. Burfoot RK, Jensen CJ, Field J, Stankovich J, Varney MD, Johnson LJ, Butzkueven H, Booth D, Bahlo M, Tait BD, Taylor BV, Speed TP, Heard R, Stewart GJ, Foote SJ, KILPATRICK TJ, Rubio JP. SNP mapping and candidate gene sequencing in the class I region of the HLA complex: searching for multiple sclerosis susceptibility genes in Tasmanians. Tissue Antigens. 2008 Jan;71(1):42-50.
5. Binder MD, Cate HS, Prieto AL, Kemper D, Butzkueven H, Gresle MM, Cipriani T, Jokubaitis VG, Carmeliet P, Kilpatrick TJ. Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelination. J Neurosci. 2008; 28(20):5195-206.
6. McKay FC, Swain LI, Schibeci SD, Rubio JP, KILPATRICK TJ, Heard RN, Stewart GJ, Booth DR. Haplotypes of the interleukin 7 receptor alpha gene are correlated with altered expression in whole blood cells in multiple sclerosis. Genes Immun. 2008 9(1):1-6.
7. McKay FC, Swain LI, Schibeci SD, Rubio JP, Kilpatrick TJ, Heard RN, Stewart GJ, Booth DR. CD127 immunophenotyping suggests altered CD4(+) T cell regulation in primary progressive multiple sclerosis. J Autoimmun. 2008; 31(1):52-8.
8. Wu QZ, Yang Q, Cate HS, Kemper D, Binder M, Wang HX, Fang K, Quick MJ, Marriott M, KILPATRICK TJ, Egan GF. MRI identification of the rostral-caudal pattern of pathology within the corpus callosum in the cuprizone mouse model. J Magn Reson Imaging. 2008 27(3):446-53.
9. Wong AW, Willingham M, Xiao J, Kilpatrick TJ, Murray SS. The Neurotrophin Receptor Homolog-2 regulates Nerve Growth Factor signaling. J Neurochem. 2008; 106(4):1964-76.
10. Khan F, Pallant JF, Brand C, Kilpatrick TJ. Effectiveness of Rehabilitation Intervention in persons with Multiple sclerosis: A Randomized Controlled Trial. J Neurol Neurosurg Psychiatry.  2008; 79(11):1230-5
11. Marriott MP, Emery B, Cate HS, Binder MD, Kemper D, Wu Q, Kolbe S, Gordon IR, Wang H, Egan G, Murray S, Butzkueven H, KILPATRICK TJ.Leukemia inhibitory factor signaling modulates both central nervous system demyelination and myelin repair. Glia. 2008 56(6):686-98.
12. Tan SS, Kalloniatis M, Truong HT, Binder MD, Cate HS, Kilpatrick TJ, Hammond VE. Oligodendrocyte positioning in cerebral cortex is independent of projection neuron layering. Glia. 2008 Dec 5. [Epub ahead of print]
13. Van der Mei I, Ponsonby AL, Blizzard L, Dwyer T, Taylor BV, McMichael T, Butzkueven H, KILPATRICK TJ. Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia. J Neurol. 2007 May;254(5):581-90
14. Wu Q, Butzkueven H, Gresle M, Kirchhoff F, Friedhuber A, Yang Q, Wang H, Fang K, Lei H, Egan GF, Kilpatrick TJ.MR diffusion changes correlate with ultra-structurally defined axonal degeneration in murine optic nerve. Neuroimage. 2007 Oct 1;37(4):1138-47.
15. Lucas RM, Ponsonby AL, McMichael AJ, van der Mei I, Chapman C, Coulthard A, Dear K, Dwyer T, KILPATRICK TJ, Pender MP, Taylor B, Vdery P, Williams D. Observational analytic studies in multiple sclerosis: controlling bias through study design and conduct. The Australian Multicentre Study of Environment and Immune Function. Multiple Sclerosis 2007 13(7): 827-839.
16. Khan F, Turner-Stokes L, Ng L, KILPATRICK T.  Multidisciplinary rehabilitation for adults with multiple sclerosis. Cochrane Database Of Systematic Reviews (2): 2007 Art. No. CD006036
    Spain AA, Tubridy N, KILPATRICK TJ, Adams SJ and Holmes, ACN. Illness perception and health-related quality of life in multiple sclerosis. Acta Neurol Scand. 2007 Nov;116(5):293-9
17. Lucas RM, Ponsonby AL, McMichael AJ, van der Mei I, Chapman C, Coulthard A, Dear K, Dwyer T, KILPATRICK TJ, Pender MP, Taylor B, Vdery P, Williams D. Observational analytic studies in multiple sclerosis: controlling bias through study design and conduct. The Australian Multicentre Study of Environment and Immune Function. Multiple Sclerosis 2007 13(7): 827-839.
18. Khan F, Turner-Stokes L, Ng L, KILPATRICK T.  Multidisciplinary rehabilitation for adults with multiple sclerosis. Cochrane Database Of Systematic Reviews (2): 2007 Art. No. CD006036
19. Rubio JP, Bahlo M, Stankovich J, Burfoot RK, Johnson LJ, Huxtable S, Butzkueven H, Lin L, Taylor BV, Speed TP, KILPATRICK TJ, Mignot E, Foote SJ. Analysis of extended HLA haplotypes in multiple sclerosis and narcolepsy families confirms a predisposing effect for the class I region in Tasmanian MS patients. Immunogenetics. 2007 Mar;59(3):177-86.
20. Emery B, Merson TD, Snell C, Young KM, Ernst M, Kilpatrick TJ. SOCS3 negatively regulates LIF signaling in neural precursor cells. Mol Cell Neurosci. 2006 Apr;31(4):739-47.
21. Emery B, Cate HS, Marriott M, Merson T, Binder MD, Snell C, Soo PY, Murray S, Croker B, Zhang J-G, Alexander WS, Cooper H, Butzkueven H  and KILPATRICK TJ. Suppressor of cytokine signaling 3 limits  protection of leukemia inhibitory factor receptor signaling against  central demyelination. Proc Natl Acad Sci USA. 2006  103(20):7859-64.
22. Emery B, Butzkueven H, Snell C, Binder M, KILPATRICK TJ.  Oligodendrocytes exhibit selective expression of suppressor of cytokine signaling genes and signal transducer and activator of transcription 1 independent inhibition of interferon-gamma-induced toxicity in response to leukemia inhibitory factor. Neuroscience. 2006;137(2):463-72.
23. Chapman C, Tubridy N, Cook MJ, Mitchell PJ, MacGregor LR, Lovelock C, Litewka L, Sedal L, KILPATRICK TJ, Butzkueven H. Short-term effects of methylprednisolone on cerebral volume in multiple sclerosis relapses. J Clin Neurosci. 2006 Jul;13(6):636-8.
24. Butzkueven, H, Emery B, Cipriani C, and KILPATRICK T.J. Endogenous Leukemia Inhibitory Factor production limits autoimmune demyelination and oligodendrocyte loss. Glia. 2006 May;53(7):696-703.
    Stankovich J, Cox CJ, Tan RB, Montgomery DS, Huxtable SJ, Rubio JP, Ehm MG, Johnson L, Butzkueven H, KILPATRICK TJ, Speed TP, Roses AD, Bahlo M, Foote SJ. On the utility of data from the International HapMap Project for Australian association studies. Hum Genet. 2006 Mar;119(1-2):220-2.
25. Ponsonby AL, Dwyer T, van der Mei I, Kemp A, Blizzard L, Taylor B, KILPATRICK T, Simmons R.Asthma onset prior to multiple sclerosis and the contribution of sibling exposure in early life. Clin Exp Immunol. 2006 Dec;146(3):463-70.
26. Martin, C, Phillips, B, KILPATRICK, T, Butzkueven, H, Tubridy, N, McDonald, E., Galea, M. Gait and balance impairment in early multiple sclerosis in the absence of clinical Disability.  Mult Scler. 2006 Oct;12(5):620-8.
27. Khan F, McPhail T, Brand C, Turner-Stokes L, KILPATRICK T. Multiple sclerosis: disability profile and quality of life in an Australian community cohort.  Int J Rehabil Res. 2006 Jun;29(2):87-96.
28. Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, Achiti I, Confavreux C, Coustans M, le Page E, Edan G, McDonnell GV, Hawkins S, Trojano M, Liguori M, Cocco E, Marrosu MG, Tesser F, Leone MA, Weber A, Zipp F, Miterski B, Epplen JT, Oturai A, Sorensen PS, Celius EG, Lara NT, Montalban X, Villoslada P, Silva AM, Marta M, Leite I, Dubois B, Rubio J, Butzkueven H, KILPATRICK T, Mycko MP, Selmaj KW, Rio ME, Sa M, Salemi G, Savettieri G, Hillert J, Compston DA. Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity.  Neurology. 2005 Apr 12;64(7):1144-51
29. Ponsonby AL, van der Mei I, Dwyer T, Blizzard L, Taylor B, Kemp A, Simmons R, KILPATRICK TJ, Exposure to infant siblings during early life and risk of multiple sclerosis. JAMA 2005 Jan 26;293(4):463-9
30. Gresle MM, Shaw G, Jarrott B, Alexandrou EN, Friedhuber A, Kilpatrick TJ, Butzkueven H. Validation of a novel biomarker for acute axonal injury in experimental autoimmune encephalomyelitis. J Neurosci Res. 2008; 86(16):3548-55.Foote SJ, Rubio JP, Bahlo M, KILPATRICK TJ, Speed TP, Stankovich J. Burfoot R, Butzkueven H, Johnson L, Wilkinson C, Taylor B, SaleM, van der Mei IA, Dickinson JL, Groom P. Multiple sclerosis: a haplotype association study. Novartis Found Symp. 2005;267:31-9
31. Grigg A, Tubridy NJ, Szer J, Mitchell P, Butzkueven H, Shuttleworth P, KILPATRICK TJ. Cladribine followed by autologous stem cell transplantation in progressive multiple sclerosis Internal Medical Journal 2004;34:66-9.
32. Coulson EJ, Reid K, Shipham K, Morley S, Kilpatrick TJ, Bartlett PF. The role of neurotransmission and the chopper domain in p75 NTR death signaling Progress in Brain Research 2004;146:41-62.
33. Taylor I, Butzkueven H, Litewka L, Cook M, Mitchell P, Kilpatrick TJ, Tubridy N. Serial MRI in multiple sclerosis: A prospective pilot study of lesion load, whole brain volume and thalamic atrophy J. Clin. Neurosci 2004;11:153-8.
34. Rubio JP, Bahlo M, Tubridy N, Wilkinson C, Johnson L, Butzkueven H, Marriott M, Carey J, Mraz G, Tait B, Speed TP, Foote SJ, Kilpatrick TJ. A common ancestral susceptibility haplotype in the HLA complex for multiple sclerosis and hemochromatosis. Hum Genet. 2004 May;114(6):573-80.
35. Petratos S , Gonzales MF, Azari MF, Marriott M, Minichiello RA, Shipham KA, Profyris C, Nicolaou A, Boyle A, Cheema SS, Kilpatrick TJ. Expression of the low affinity neurotrophin receptor p75NTR on oligodendrocyte progenitors in chronic active MS lesions Glia. 2004 Oct;48(1):64-75.
36. Turner BJ, Murray SS, Piccenna LG, Lopes EC, Kilpatrick TJ, Cheema SS. Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice. J Neurosci Res. 2004 Oct 15;78(2):193
37. Kilpatrick TJ, Butzkueven H, Emery B, Marriott M, Taylor BV, Tubridy N. Neuroglial responses to CNS injury: prospects for novel therapeutics. Expert Rev Neurother. 2004 Sep;4(5):869-78.
38. Pitman M, Emery B, Binder M, Wang S, Butzkueven H, Kilpatrick, TJ. LIF Receptor Signalling Modulates Neural Stem Cell Renewal. Mol Cell Neurosci. 2004 Nov;27(3):255-66.
39. Ponsonby AL, van der Mei I, Dwyer T , Blizzard L, Taylor B , Kemp A, Simmons R, Kilpatrick TJ. Exposure to infant siblings during early life and risk of multiple sclerosis. JAMA 2005 Jan 26;293(4):463-9
40. Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, Achiti I, Confavreux C, Coustans M, le Page E, Edan G, McDonnell GV, Hawkins S, Trojano M, Liguori M, Cocco E, Marrosu MG, Tesser F, Leone MA, Weber A, Zipp F, Miterski B, Epplen JT, Oturai A, Sorensen PS, Celius EG, Lara NT, Montalban X, Villoslada P, Silva AM, Marta M, Leite I, Dubois B, Rubio J, Butzkueven H, Kilpatrick T, Mycko MP, Selmaj KW, Rio ME, Sa M, Salemi G, Savettieri G, Hillert J, Compston DA. Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology. 2005 Apr 12;64(7):1144-51

Laboratory Photos

Simon Murray