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RTD info logoMagazine on European Research N° 43 - November 2004   
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MEDICAL RESEARCH 
Title  Reducing congestion on the inflammation highways

Why are leukocytes, or white blood cells, attracted to areas of inflammation and how do they travel to them? By changing their migratory habits, can we stop the chronic inflammation associated with many diseases? A new European Network of Excellence made up of 13 institutes from five EU countries (DE, ES, FR, IT, UK), plus Switzerland and Israel, has given itself four years to come up with the initial answers to these questions.

Mastocyte: this immune cell that contains many granulations in its cytoplasm plays an important role in immediate hypersensitivity. These granulations release mediators – such as histamine – at the time of the allergic response. © David, B. / Institut Pasteur
Mastocyte: this immune cell that contains many granulations in its cytoplasm plays an important role in immediate hypersensitivity. These granulations release mediators – such as histamine – at the time of the allergic response.
© David, B. / Institut Pasteur
Asthma, arteriosclerosis and Alzheimer’s are three diseases that, while affecting very different organs, are surprisingly similar in terms of biological mechanisms. They all involve the chronic inflammation of an organ: the lung, the arterial wall and certain regions of the brain respectively. This causes the immune system to react to the extent that it attacks the tissue of the body it is supposed to be protecting against external aggression. Auto-immune diseases are the ultimate expression of this kind of disorder, new consequences of which are regularly coming to light. On 25 August, for example, the British publication Nature published a study carried out by an Israeli group associating chronic inflammation linked to irritating substances in the environment with the appearance of cancers. 

Activating defence mechanisms
As defensive reactions by cell tissue against a foreign aggression (infections, burns, allergies, etc.), the biological mechanisms of ordinary inflammation are quite well described. It all starts with a kind of warning signal emitted by certain leukocytes in the form of a tiny molecule known as histamine. This hormone triggers an immediate inflammatory response, in particular the dilatation of blood vessels, that causes the familiar rashes associated with allergies. In its attempts to repair the damage, the histamine will also activate other categories of leukocytes – lymphocytes and macrophages – that secrete a wide variety of glycoproteins of the cytokine family. Both mediating and amplifying agents, the cytokines in turn trigger the mobilisation of more leukocytes that begin to migrate to the site of the inflammation. 

The activation of the endothelial cells that line the blood vessel walls plays a key role in the patho-physiology of many forms of chronic inflammation, such as rheumatoid arthritis. They then take on a cubic shape and compete with the migration of leukocytes to the inflamed tissue. These cells are a major biological target for the development of anti-inflammatory treatments.
The activation of the endothelial cells that line the blood vessel walls plays a key role in the patho-physiology of many forms of chronic inflammation, such as rheumatoid arthritis. They then take on a cubic shape and compete with the migration of leukocytes to the inflamed tissue. These cells are a major biological target for the development of anti-inflammatory treatments.
This process is believed to be at the origin of a state of chronic inflammation. But what is it that triggers this mechanism? It was to answer this question that a European Network of Excellence known as Main-NoE (Migration and Inflammation Network of Excellence) was launched on 18 June of this year, at the instigation of Ruggero Pardi of the Fondazione Centro San Raffaele del Monte Labor, a world-renowned biomedical research centre based in Milan (IT).

“Dozens of European laboratories are currently working, on an uncoordinated basis, on the various mechanisms of inflammation. Some are specialised in the synthesising mechanisms of a particular cytokine, others are interested in their receptors or in their action on lymphocyte differentiation, and others, finally, are looking at the key problem of their action on migration. I contacted several of my colleagues who had already worked in partnership on a previous European project. We chose to draw on the dynamic of the new tools for co-operation created by the Sixth Framework Programme to concentrate systematically on this latter process alone. We hope in this way to achieve the best degree of integration among the participating scientists,” explains Pardi. 

Lines of attack

The Main-NoE is pursuing four lines of attack in investigating the migratory phenomenon of leukocytes. 
  • The first, seemingly simple, question is how do researchers study cell migration? Tools Development is seeking to provide them with the most effective techniques, such as video-microscopy that makes it possible to observe cell or biocaptor migration ‘live’ and, thus, measure the concentration of chemical messengers in the cellular environment. 
  • Question number two: how do leukocytes travel? We know they form pseudopods that attach them to the extracellular matrix, after which they retract, drawing the cell body with them. The Target Identification programme is seeking to identify the proteins at work in this process, especially cell skeleton and matrix proteins. But do the migratory mechanisms depend on the type of cell or the type of pathology? To date, this problem has received little attention. Different laboratories use different cell types and different culture conditions when carrying out their in-vitro tests, making any comparison of results a tricky task. 
  • This leads on to the third area of research, namely Target Validation. This aims to develop standardised and clinically pertinent tests to study the action of cytokine cocktails. DNA chips that make it possible to analyse the expression of all the genes known to be involved in cell migration will also be developed to compare the genetic profiles of different leukocytes during their migration. 
  • Finally, there is the question of whether or not these mechanisms lend themselves to pharmacological modification for therapeutic purposes. Current anti-inflammatory medicines often present serious side effects and sometimes reduce natural immune defences. The Drug Development programme aims to promote the network’s research, in association with two biotechnology companies – Endocube SAS (FR) and Bioxell SpA (IT) – which will benefit from a priority licence on patents registered by the network’s researchers and will ensure the pre-clinical development of the most interesting molecules. 
Cross-section of asthmatic bronchial tubes. © David, B. / Institut Pasteur
Cross-section of asthmatic bronchial tubes.
© David, B. / Institut Pasteur
Nurturing a healthy body of knowledge
This ambitious programme could not, of course, function without the costly tools that are essential to modern ‘big biology’. Joint services, such as cell imaging, proteomics, DNA chip and bio-informatics services, will provide this essential merging of resources. Finally, the Main-NoE will organise training seminars, designed for post-doctorates in particular, on the mechanisms of chronic inflammation. 

With Union funding of €10 million over the next four years, a network of this kind requires an effective logistics organisation. The Italian Science Park of San Raffael, with long experience of managing biotech R&D programmes, is providing the administrative infrastructure. A steering committee, headed by Ruggero Pardi and Anne Ridley (University College London), meets twice a month, by videoconference, to discuss progress and allocate funds on the basis of requests from the around 180 researchers involved. “Closer working relationships are being forged within the field of technology, as well as science. That is why, when financing the teams participating in the Main-NoE, priority must be awarded to those that propose a very integrated project and/or the development of investigation tools that can be useful to all network participants," explains Pardi. He also says he is "very excited by this new organisation to promote the excellence of European research". 

An external advisory committee, headed by Alan Rick Horwitz of the University of Virginia (USA), will advise the managing team. The three other committee members will also be American. This is because Main-NoE seeks to be a partner, and not a rival, of the US initiative known as the Cell Migration Consortium (CMC). "MAIN and CMC will share information and technology platforms and will develop a coordinated programme of scientific events so as to communicate their results to a wider audience of experts," stresses Pardi. "Information will also be provided to patients who are suffering from the often disabling effects of chronic inflammatory diseases."


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  TO FIND OUT MORE  
 
  • Site of the MAIN-NoE project
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      CONTACTS  
     
  • Ruggero Pardi, Fondazione Centro San Raffaele del Monte Labor
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