David BrownDr. David Brown has an abiding interest in the examination of immune regulation, particularly as it applies to the central nervous system (CNS). Dr Brown’s interest in neuroinflammation was sparked when he noticed that many of his patients with systemic autoimmune disease had significant neurological dysfunction, ranging from depression and personality change to frank neuroinflammatory disease. After his postdoctoral studies at the Salk Institute, USA, Dr Brown returned to Australia to establish his own laboratory at The St Vincent’s Centre for Applied Medical Research. Here using a number of unique models of neurionflammatory disease, he is examining the regulation of the immune system and its interaction with the CNS. Insights that are being gained using these models are applicable to many autoimmune diseases and form a stepping stone to new treatments for these diseases.

Using animal modes related to and including experimental autoimmune encephalomyelitis, and animal model of Multiple Sclerosis, Dr Brown has defined new pathways of immune cell traffic through the brain that are capable of being modified. Modification of these pathways provide an opportunity to change immunity against the brain and treat diseases such as Multiple Sclerosis. In addition to defining how the immune cells interact and travel through the CNS, Dr Brown has an interest in several molecules including macrophage inhibitory cytokine-1 (MIC-1/GDF15) and CCAAT enhancer binding protein delta (CEBPD).

The transcription factor CEBPD is a regulator of inflammation that is not usually expressed at high levels. During inflammation it is highly expressed, controls the immune response and is found at higher concentrations in the blood and brain of MS patients. In his animal models, Dr Brown found that protein levels of CEBPD could be reduced in circulating blood cells that, in turn, reduced CNS disease. Future studies are planned to develop gene therapeutic approaches targeting CEBPD in immune cells outside the brain to treat MS.

The other Molecule that Dr Brown is interested in is MIC-1/GDF15. He has authored many high impact factor papers defining the utility of macrophage inhibitory cytokine-1 (MIC-1/GDF15) measurement in blood. He has had a long term interest in the examination of MIC-1/GDF15 in many diseases and recently found it’s measurement could predict people at higher risk of death within the next 14 years. He is now applying his extensive knowledge of neuroinflammation and the models of disease he has established in his laboratory to study MIC-1/GDF15 and how it interact with the CNS and the immune response against it. Currently it appears MIC-1/GDF15 is a promising therapy for autoimmune diseases.

Current Research Projects

  • Cellular mechanisms of CNS immunoregulation
  • CEBPD in CNS immunoregulation
  • MIC-1/GDF15 in CNS immunoregulation
  • Macrophage inhibitory cytokine-1 in immunity
  • Macrophage inhibitory cytokine-1 in disease
  • Inflammation in spinal cord injury

Selected Publications

  • Brown DA, Sawchenko PE. Time course and distribution of inflammatory and neurodegenerative events suggest structural bases for the pathogenesis of experimental autoimmune encephalomyelitis. J Comp Neurol. 2007;502:236-260.
  • Wiklund FE, Bennet AM, Magnusson PK, Eriksson UK, Lindmark F, Wu L, Yaghoutyfam N, Marquis CP, Stattin P, Pedersen NL, Adami HO, Gronberg H, Breit SN, Brown DA. Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality. Aging Cell. 2010;9:1057-1064.
  • Brown DA, Breit SN, Buring J, Fairlie WD, Bauskin AR, Liu T, Ridker PM. Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study. Lancet. 2002;359:2159-2163.
  • Tong S, Marjono B, Brown DA, Mulvey S, Breit SN, Manuelpillai U, Wallace EM. Serum concentrations of macrophage inhibitory cytokine 1 (MIC 1) as a predictor of miscarriage. Lancet. 2004;363:129-130.
  • Brown DA, Moore J, Johnen H, Smeets TJ, Bauskin AR, Kuffner T, Weedon H, Milliken ST, Tak PP, Smith MD, Breit SN. Serum macrophage inhibitory cytokine 1 in rheumatoid arthritis: A potential marker of erosive joint destruction. Arthritis Rheum. 2007;56:753-764.
  • Johnen H, Lin S, Kuffner T, Brown DA, Tsai VW, Bauskin AR, Wu L, Pankhurst G, Jiang L, Junankar S, Hunter M, Fairlie WD, Lee NJ, Enriquez RF, Baldock PA, Corey E, Apple FS, Murakami MM, Lin EJ, Wang C, During MJ, Sainsbury A, Herzog H, Breit SN. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med. 2007;13:1333-1340
  • Breit SN*, Johnen H*, Cook AD, Tsai VWW, Mohammad MG, Kuffner T, Zhang HP, Marquis CP, Jiang L, Glen Lockwood G, Lee-Ng M, Husaini Y, Wu L, John A Hamilton JA, Brown DA*. The TGF-b superfamily cytokine, MIC-1/GDF15: a pleotrophic cytokine with roles in inflammation, cancer and metabolism. Growth Factors. 2011 29:187-95.
  • Breit SN, Carrero JJ, Tsai VWW, Yagoutifam N, Luo W, Kuffner T, Bauskin AR, Wu L, Jiang L, Barany P, Heimburger O, Murikami M, Apple FS, Marquis CP, Macia L, Lin S, Sainsbury A, Herzog H, Law M, Stenvinkel P*, Brown DA*. Macrophage inhibitory cytokine-1 (MIC-1/GDF15) and mortality in end stage renal disease. Nephrol Dial Transplant. 2011 Sep 22. [Epub ahead of print].
  • Tsai VWW*, Mohammad MG*, Tolhurst O, Breit SN, Sawchenko PE, Brown DA. CCAAT/enhancer binding protein-δ expression by dendritic cells regulates CNS autoimmune inflammatory disease J Neurosci. 2011 In Press

PubMed publication for Dr Brown

External Funding Agencies
NHMRC
Multiple Sclerosis Research Australia
Prostate Cancer Foundation of Australia
NSW Government
SpinalCure Australia

Licensed discoveries
Measurement of serum levels of MIC-1/GDF15 for prognosis and management of cardiovascular diseases has been licensed to Hoffman La Roche.

Licensing opportunities
Measurement of serum levels of MIC-1/GDF15 for prognosis and management of cancer.

Current Laboratory Members
Lab Head

David Brown

Postdoctoral Fellows
Mohammad Mohammad

Research Assistants
Ornella Tolhurst

Contact Information
Anna Irvine
T: +61 (0)2 8382 4952
F: +61 (0)2 8382 4971
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