Macrophage Inhibitory Cytokine 1: A new treatment for MS?

Associate Professor David Brown

The University of NSW, NSW

| Better treatments | Immunology | Project | 2014 | Investigator Led Research |
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Summary

Macrophage Inhibitory Cytokine 1 (MIC-1/GDF15) is a protein that was discovered in Australia through the research program in which Associate Professor David Brown is involved. It is now being internationally developed as a new therapy for a number of diseases (including obesity and inflammation).

Inflammatory diseases, such as MS, are characterised by disruptions to both the innate and adaptive immune systems. The most difficult to treat forms of MS, which are relentlessly progressive, appear to be mediated by innate immune cells such as dendritic cells and the microglia that are resident in the brain. There are currently no effective treatments for the progressive forms of MS.

Preliminary evidence from Associate Professor Brown’s laboratory suggests that MIC-1/GDF15 modulates the innate immune system and therefore has the potential to be an effective treatment for progressive MS. Completion of this project will determine the mechanisms of action of MIC-1/GDF15, and the consequences of its expression on innate and adaptive immune responses in MS. Additionally, Associate Professor Brown will provide proof-of-principle for MIC-1/GDF15 as a therapeutic agent for autoimmune diseases such as MS.

Project Outcomes

The first stage of Associate Professor Brown’s project used immune cells grown in the laboratory to determine whether MIC-1/GDF15 has an effect on reducing the activity of these cells. Results from this stage will then inform the second phase of study, where MIC-1/GDF15 will be tested in an MS-like disease in mice to determine whether it can reduce disease.

The first two stages of Associate Professor Brown’s project are ongoing and early work has shown the effects of MIC-1/GDF15 on different immune cell types, and how this would influence overall immune system functioning in an MS-like disease. Associate Professoressor Brown is currently undertaking proof-of-principle analyses and confirming replication analyses to verify his results and looking for avenues to rapidly translate this research from the laboratory to the clinic. The identification of the mechanism by which MIC-1/GDF15 acts and confirmation of its therapeutic potential in models of MS will not only provide important insights into the pathogenic mechanisms of MS, but also provides the rare opportunity to rapidly progress experimental results into direct benefits for people with MS.

Publications

  • Fuchs T, Trollor JN, Crawford J, Brown DA, Baune BT, Samaras K, Campbell L, Breit SN, Brodaty H, Sachdev P, Smith E. Macrophage inhibitory cytokine-1 is associated with cognitive impairment and predicts cognitive decline - the Sydney Memory and Ageing Study. Aging Cell. doi: 10.1111/acel.12116.
  • Bechter K, Brown DA, Neuroinflammation in psychiatric disorders – Evidence from research and clinic. Neurology, Psychiatry and Brain Research. 2013;9: 139-40 (Editorial)
  • Mohammad, M.G., Tsai, V.W.W., Ruitenberg, M.J., Hassanpour, M., Li, H., Hart, P.H., Breit, S.N., Sawchenko, P.E., & Brown, D.A. (2014). Immune cell trafficking from the brain maintains CNS immune tolerance. The Journal of Clinical Investigation. 124(3), 1.
  • Tsai VW, Manandhar R, Jørgensen SB, Lee-Ng KK, Zhang HP, Marquis CP, Jiang L, Husaini Y, Lin S, Sainsbury A, Sawchenko PE, Brown DA*, Breit SN*. The Anorectic Actions of the TGFβ Cytokine MIC-1/GDF15 Require an Intact Brainstem Area Postrema and Nucleus of the Solitary Tract. PLoS One. 2014 Jun 27;9(6):e100370.
  • Tsai VW, Macia L, Johnen H, Kuffner T, Manadhar R, Jørgensen SB, Lee-Ng KK, Zhang HP, Wu L, Marquis CP, Jiang L, Husaini Y, Lin S, Herzog H, Sainsbury A*, Breit SN*, Brown DA*. TGF-b Superfamily Cytokine MIC-1/GDF15 Is a Physiological Appetite and Body Weight Regulator. PLoS One. 8:e55174. IF= 4.09
  • Husaini Y, Lockwood GP, Nguyen T, Tsai VWW, Mohammad MG, Russell PJ, Brown DA*, Breit SN*. Macrophage Inhibitory Cytokine-1 (MIC-1/GDF15) Gene Deletion Promotes Cancer Growth in TRAMP Prostate Cancer Prone Mice. PLoS One (in Press) IF= 4.09.
  • Jiang J, Wen W, Brown DA, Crawford J, Thalamuthu A, Smith E, Breit SN, Liu T, Zhu W, Brodaty H, Baune BT, Trollor JN, Sachdev PS. The relationship of serum macrophage inhibitory cytokine - 1 levels with gray matter volumes in community-dwelling older individuals. PLoS One. 13;10(4):e0123399. IF= 4.09
  • Fisher OM, Levert-Mignon AJ, Lord SJ, Lee-Ng KK, Botelho NK, Falkenback D, Thomas ML, Bobryshev YV, Whiteman DC, Brown DA, Breit SN, Lord RV.MIC-1/GDF15 in Barrett's oesophagus and oesophageal adenocarcinoma. Br J Cancer. 2015 112(8):1384-91.
  • Tsai VWW, Macia L, Feinle-Bisset C, Manandhar R, Astrup A, Raben A, Lorenzen JK, Schmidt PT, Wiklund F, Pedersen NL, Campbell L, Kriketos A, Xu A, Pengcheng Z, Jia W, Lee-Ng M, Zhang HP, Marquis CP, Husaini Y, Beglinger C, Lin S, Herzog H, Brown DA*, Sainsbury A*, Breit SN*. Serum levels of human MIC-1/GDF15 vary in a diurnal pattern, do not display a profile suggestive of a satiety factor and are related to BMI. PLoS One. In Press.
  • Jiang J, Trollor JN, Brown DA, Crawford JD, Thalamuthu A, Smith E, Breit SN, Liu T, Brodaty H, Baune BT, Sachdev PS, Wen W. An inverse relationship between serum macrophage inhibitory cytokine-1 levels and brain white matter integrity in community-dwelling older individuals. Psychoneuroendocrinology. 2015 62:80-88.
  • Sasson SC, McGill K, Wienholt L, Carr A, Brown DA, Kelleher AD, Breit SN, Sewell WA. Comparison of the Freelite serum free light chain (SFLC) assay with serum and urine electrophoresis/immunofixation and the N Latex FLC assay. Pathology. 2015 47(6):564-9.
  • Geldenhuys S, Mohammad MG, Li H, Hassanpour M, Ng RLX, Scott NM, Lucas RM, Brown DA and Hart PH. UV Irradiation of Skin Regulates a Murine Model of Multiple Sclerosis J Mult Scler (2015) 2 144
  • Tsai VW, Lin, Brown DA, Salis A, Breit SN. Anorexia-cachexia and obesity treatment may be two sides of the same coin: Role of the TGF-b superfamily cytokine MIC-1/GDF15. Int J Obes. 2015 Dec 1. doi: 10.1038/ijo.2015.242. [Epub ahead of print]

Updated: 12 April 2016

Updated: 06 January, 2014

Investigator

Grant Awarded

  • Project Grant

Total Funding

  • $250,000

Duration

  • 3 years over 2014 - 2016

Funding Partner

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