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For more information, go to www.arthritisresearchuk.org

Newcastles arthritis agenda a postgraduate focus

Published on 01 April 2009
Source: Arthritis Today

PhD students James Locke and Caroline Wilson

A multidisciplinary blend of basic science and clinical research drives an impressively successful research programme within the Musculoskeletal Research Group of Newcastle University’s Faculty of Medical Sciences.

This innovative research hub has established itself as a highly efficient, patient-focussed centre that places teamwork and innovative collaboration at the forefront of its work ethos. Arthritis Today looks at how the first tier of this thriving academic group, the postgraduate students, are progressing across a range of Arthritis Research UK-funded PhD projects.

An impressive reputation

Newcastle University’s Faculty of Medical Sciences boasts an impressive reputation for its achievements in strategic planning, translational research, and academic teaching. Rated very highly in the recent 2008 Research Assessment Exercise, and awarded prestigious National Institutes for Health Biomedical Research Centre status, the faculty attracts extensive funding from Arthritis Research UK and other bodies, and enjoys expanding research and clinical research facilities.

Tim Cawston, Dean of Research and William Leech Professor of Rheumatology, sums up a major research emphasis of the faculty: “It has been said recently that life expectancy is increasing by five hours for every single day that passes. What we need to focus on is: how good will those five hours be, and how can we make them better?”

The Musculoskeletal Research Group certainly rises to this challenge by promoting a collaborative mix of basic science and clinical research projects to address the problems of arthritis and age-related musculoskeletal diseases, alongside other specialist areas in paediatric rheumatology and education research. Strong interactions between laboratory and clinical sectors ensure a good supply of vital clinical samples and excellent communication links that support their translational approach to disease research.

Up and coming research in focus

For the PhD students, research is set against a background of investigative excellence in a range of disciplines: immunotherapy, stem cell transplantation, molecular genetics, and orthopaedic science, to name just a few. This expertise and technology supports their approach to tackling key arthritis issues - identifying susceptibility and early disease, and preventing or slowing disease progress.

Immunotherapy and matrix biology are the main research areas. Immunotherapy investigates the functioning of the immune cells in health and disease and exploits this knowledge to develop therapies that can restore normal functioning or block destructive pathways. Matrix biology is concerned with the functioning of the cartilage and bone environment and how molecular interactions within this dynamic medium are responsible for cartilage and bone damage.

Reduced enzymes in osteoarthritis

Christos Gabrielides is investigating how cartilage problems in osteoarthritis (OA) may be caused by defects in cartilage cell mitochondria. Mitochondria are small organelles within the cell that are described as ‘power houses’ because they generate the chemical power for cell metabolism. As well as energy, their chemical reactions produce toxic substances called free radicals, which are very reactive and can damage other molecules.

Christos explains: “We know that mitochondrial dysfunction plays a role in OA and other diseases such as Alzheimer’s. Normally, free radicals are neutralised by powerful enzymes but we’ve discovered that in mitochondria from OA individuals, these enzyme levels are significantly reduced. We think that free radicals accumulate and damage mitochondrial genes, causing cellular malfunction and eventually cartilage breakdown. Accumulation of genetic mutations is believed to be the reason why we age and since OA and Alzheimer’s generally affect older people, this may be the cause of tissue malfunction.”

He aims to investigate the development of these mutations by studying mitochondria sourced from OA clinical samples. If the research confirms that enzyme depletion increases genetic mutations and OA progression, it may reveal new targets for therapy development.

Understanding molecular recognition

A specific division of immune cells, called B-cells, are known to play an important role in the recognition of microbes when infection occurs in the body. Recent research suggests that in rheumatoid arthritis (RA), this defence system malfunctions and B-cells may mistakenly recognise some of the body’s own molecules as ‘foreign’. This results in the immune system attacking the body - the autoimmune response.

Caroline Wilson, now in her final PhD year, has been investigating how B-cells respond to one of these body molecules, aggrecan, that makes up much of the joint cartilage matrix. Aggrecan is an important component of healthy cartilage and if it’s attacked by the immune system, cartilage structure is destroyed.

By investigating the cellular mechanisms that cause this recognition system to go wrong, Caroline hopes to produce data that will contribute to the development of drugs designed to block or even prevent disease. “We have generated a line of B-cells that recognise only aggrecan molecules so that we can study the detail of the recognition system. The aggrecan-specific B-cells are 10,000 times more efficient than ordinary B-cells at inducing an immune response. We’re using these to characterise the molecular events that promote autoimmunity.”

Achieving the aggrecan-specific model has been a large part of her research and represents a major advance in autoimmune investigation techniques that will benefit RA research as well as other autoimmune disease studies.

Vaccine possibilities for rheumatoid arthritis

Dendritic cells feature high on the list of ground breaking research topics. These are the immune cells that act like army generals, issuing orders to the army of white blood cells and coordinating the immune response. Some can order an attack whilst others can suppress an attack, and it’s this controlling ability that makes them a key focus for research purposes. 

Media coverage has had the global research community reverberating with the news that the Newcastle team, headed up by Professor John Isaacs and Dr Catharien Hilkens, had achieved the first steps in vaccine development for RA using these unique cells, with Arthritis Research UK funding.

Dendritic cells can develop into either the mature cells that promote the immune response, or the so-called tolerogenic cells that prevent immune system activity. Newcastle researchers take white blood cells from the patient and subject them to a novel in vitro technique that manipulates their differentiation into tolerogenic dendritic cells. These will be introduced back into the patient in vaccine form, by injection directly into an inflamed knee joint.

It’s hoped that this vaccine system will suppress or down-regulate the autoimmune response - using the patient’s own cells guarantees immune specificity and there are high hopes for positive outcomes. Once pilot studies are complete, larger scale clinical trials will be initiated.

Switching off inflammation

PhD students Harriet Purvis and Amy AndersonBoth postgraduate and postdoctoral students are engaged in research projects focusing on this exciting research strand. One of these students, Harriet Purvis, is investigating how the tolerogenic dendritic cells suppress the immune system in RA. The cells that launch the attack in an immune response are called T-cells and recent research has identified a new subset of these, called Th17 cells. These produce powerful inflammatory chemicals, or cytokines, including IL-17 (interleukin-17), that destroy synovial tissue and enhance bone destruction.

IL-17 is found in high concentrations in the synovial fluid of RA joints and it is suggested that switching off or slowing down the activity of these ‘bad’ Th17 cells could prevent or inhibit RA. Harriet explains: “The aim of the project is to learn how the tolerogenic dendritic cells affect Th17 cell function. If we can understand the underlying molecular mechanisms involved, we may be able to identify new targets for therapy options. In addition, we want to identify biomarkers, that is, molecules that give us some measurable indication of how well this dendritic therapy is achieving Th17 cell suppression. Then we’ll be able to measure treatment efficacy prior to overt clinical benefit".

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