A*STAR scientists bring to light mechanism of drug for infections

(Press-News.org) Contact information: Tan Yun Yun
tan_yun_yun@a-star.edu.sg
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Agency for Science, Technology and Research (A*STAR), Singapore
A*STAR scientists bring to light mechanism of drug for infections New knowledge of drug mechanism paves road to new treatment approaches for patients suffering from frequent bacterial infections 1. Scientists at A*STAR's Singapore Immunology Network (SIgN) have discovered the exact mode of action by plerixafor, a drug commonly prescribed to stimulate immune responses in patients suffering from neutropenia, which causes them to become prone to oral, skin, genital infections and in worst cases, a fatal whole-body infection . A better understanding of the drug's mechanism can improve its usage to more effectively reduce risk of infections in these patients.

2. Scientists at SIgN employed cutting-edge imaging techniques to analyze the effects of plerixafor on the white blood cell activity in the study which was published in the Journal of Experimental Medicine (JEM). Neutrophil Mobilization via Plerixafor

3. Neutropenia is a condition characterized by the lack of a type of white blood cells, also known as neutrophils , in one's blood circulation. Plerixafor increases the concentration of these white blood cells in the blood by inhibiting a protein called CXCR4. This inhibition prevents neutrophils in the blood stream from returning to the bone marrow, which is the primary compartment where the white blood cells are stored and released. It is therefore commonly accepted that the efficacy of the drug arises only from the release of these white blood cells from the bone marrow.

4. However, scientists at SIgN found that the inhibition of CXCR4 by the drug actually plays a dual role – It increases the neutrophil count in the blood through their release from the lungs, while simultaneously promoting their retention in the blood stream. Discovery of this additional mode of action not only provides a deeper understanding on the drug's mechanism, it also contributes to a more effective utilization of the drug. The ground-breaking study creates the possibility of using a combined drug treatment to maximise release of white blood cells from both the bone marrow and the lungs. The approach may be more effective in reducing the risk of bacterial infections in neutropenic patients.

5. The team leader, Dr Ng Lai Guan from SIgN said, "We have identified the precise mechanisms of plerixafor treatment, which has important implications on its usage. We can understand through this study the effectiveness or limitations of the drug on certain patients and thereafter craft new clinical approaches to better treat them. Our study forms a conceptual framework to establish improved therapeutic strategies for neutropenia."

6. Acting Executive Director of SIgN, Associate Professor Laurent Rénia, said, "Basic research as such is important for us to fully understand how drugs work, so that we can put them to best use. This is a study which can potentially be translated into clinical applications to impact the health and lives of neutropenic patients."

### Notes for editor: The research findings described in this media release can be found in the September 30, 2013 issue of the Journal of Experimental Medicine (JEM), under the title, "Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow" by Sapna Devi1*, Yiline Wang1*, Weng Keong Chew1*, Ronald Lima2, Noelia A-González3, Citra N.Z. Mattar4, Shu Zhen Chong1, Andreas Schlitzer1, Nadja Bakocevic1, Samantha Chew1, Jo L. Keeble1, Chi Ching Goh1, Jackson L.Y. Li1, Maximilien Evrard1, Benoit Malleret1, Anis Larbi1, Laurent Renia1, Muzlifah haniffa1,5, Suet Mien Tan6, Jerry K.Y. Chan4,7,8, Karl Balabanian9, Takashi Nagasawa10,11, Franҫoise Bachelerie9, Andrés Hidalgo3, Florent Ginhoux1, Paul Kubes2, and Lai Guan Ng1

1 Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, 138648 Singapore 2 Calvin, Phoebe, and Joan Snyder Institute for Infection, Immunity, and Inflammation, University of Calgary, Alberta T2N 1N4, Canada 3 Department of Epidemiology, Atherothrombosis and Imaging, Fundaciόn Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain 4 Experimental Fetal Medicine Group, Yoo Loo Lin School of Medicine, National University of Singapore, 119228 Singapore 5 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK 6 School of Biological Sciences, Nanyang Technological University, 637551 Singapore 7 Department of Reproductive Medicine, KK Women's and Children's Hospital, 229899 Singapore 8 Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 169857 Singapore 9 Inserm Unite Mixte de Recherche (UMR) S996, Universitei Paris-Sud, Laboratory of Excellence in Research on Medication and Innovative Therapeutics, 92140 Clamart, France 10 Department of Immunobiology and Hermatology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Singapore 11 Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Tokyo 102-0076, Japan

*These authors contributed equally to this work

Full text of the article can be accessed from http://www.jem.org/cgi/doi/10.1084/jem.20130056

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About the Singapore Immunology Network (SIgN) The Singapore Immunology Network (SIgN), officially inaugurated on 15 January 2008, is a research consortium under the Agency for Science, Technology and Research (A*STAR)'s Biomedical Research Council. The mandate of SIgN is to advance human immunology research and participate in international efforts to combat major health problems. Since its launch, SIgN has grown rapidly and currently includes 250 scientists from 26 different countries around the world working under 28 renowned principal investigators. At SIgN, researchers investigate immunity during infection and various inflammatory conditions including cancer and are supported by cutting edge technological research platforms and core services. Through this, SIgN aims to build a strong platform in basic human immunology research for better translation of research findings into clinical applications. SIgN also sets out to establish productive links with local and international institutions, and encourage the exchange of ideas and expertise between academic, industrial and clinical partners and thus contribute to a vibrant research environment in Singapore. For more information about SIgN, please visit http://www.sign.a-star.edu.sg.

About the Agency for Science, Technology and Research (A*STAR) The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that fosters world-class scientific research and talent to drive economic growth and transform Singapore into a vibrant knowledge-based and innovation driven economy. In line with its mission-oriented mandate, A*STAR spearheads research and development in fields that are essential to growing Singapore's manufacturing sector and catalysing new growth industries. A*STAR supports these economic clusters by providing intellectual, human and industrial capital to its partners in industry. A*STAR oversees 20 biomedical sciences and physical sciences and engineering research entities, located in Biopolis and Fusionopolis as well as their vicinity. These two R&D hubs, house a bustling and diverse community of local and international research scientists and engineers from A*STAR's research entities as well as a growing number of corporate laboratories. For more information about A*STAR, please visit http://www.a-star.edu.sg.