Back to basics: University College London

Published on 01 October 2009
Source: Arthritis Today

Professor Tim Arnett

University College London holds an impressive reputation for its strong track record in translational research. Interdisciplinary collaboration between immunology, rheumatology, gene therapy and molecular biology means that research expertise and technical facilities can be optimised to tackle the challenges of arthritis and inflammatory disease. A fascinating range of innovative approaches is currently yielding new insights into disease mechanisms and opening up new possibilities for therapy approaches.

Recognising ‘self’

Most rheumatoid arthritis (RA) patients today have a clear understanding of the disease that causes their pain and immobility. They know that their own immune system is attacking the body and that research is needed to understand why this happens and how to prevent it or halt it.

The immune system normally recognises the invaders that are foreign to the body – bacteria, viruses, or chemicals – and attacks them. It leaves the body’s own tissues or ‘self’ alone. In rheumatoid arthritis, both ‘self’ and ‘non-self’ cells are attacked in the same way suggesting that the immune system doesn’t recognise the difference between them. Understanding how the recognition mechanism works normally is key to being able to understand what happens when it goes wrong and developing therapies to correct or counter it.

An army of white cells

At University College London’s Department of Immunology and Pathology, Dr David Escors, Arthritis Research UK non-clinical career development research fellow, is tackling this problem using novel gene therapy techniques. He explains: “The white blood cells in our body are like an immune system army. There are different types of white blood cell just as there are different roles and ranks in the army. Dendritic cells are very important in terms of ordering other white cells – they’re like the army generals. They initiate the battles and direct large numbers of soldier white cells to fight against the invaders. If they give the wrong orders, the soldier cells will attack indiscriminately, killing healthy cells too. The reason that the wrong orders are given is because the generals have the wrong genetic programming. To change the orders given out by them, we need to alter their genes.”

Gene therapy expertise

Gene therapy is rapidly becoming a serious treatment option for some disease states. It’s possible to insert new genes into the body that can instruct faulty cells to work normally. Collaboration with the Department of Rheumatology has combined the group’s expertise in gene therapy techniques with the most advanced immunological knowledge.

Dr Escors studies viruses and has expertise in techniques using harmless viruses to transport genetic material into cells that have faulty genetic programming. The correct genetic material can be transferred into immune cells where it ‘teaches’ the cells how to recognise ‘self’ and ‘non-self’, and stops them from attacking healthy tissue.

Corrective therapy for the immune system

Lentiviruses are viruses that are very efficient at targeting and entering cells and introducing their genetic material. The virus has all its disease-causing material removed and replaced with the corrective genes, becoming a non-infectious gene-carrier (lentivector). Dr Escors has successfully used a lentivector to replace the genetic material in dendritic cells and is now ready to progress to human cell testing.

“We want to work out exactly which genetic instructions control the recognition part of the immune attack,” says Dr Escors, “so that we can engineer therapies that alter just these specific components.

First we have to test the lentivector on patient cells in culture and make sure that we get the effects that we want. Then, we’ll test the therapy in clinical trials.

“Making lentivectors is expensive rather than difficult,” he adds. “UCL is currently involved in setting up a facility to provide more economic production methods for scaling up manufacture of clinical trial grade material for human use. Lentivectors are already being used in other human clinical applications, including cancer trials, and so we already have the advantage of safety and performance information from those studies.”

Flagging up infection

Cells that become infected by microorganisms have to let the immune system know that they are infected so that it can recognise them and destroy them. They do this by displaying protein ‘flags’ on their surface that alert the immune system. The flags are made inside the cells and when the cells become infected, the flags are transported to the cell surface and displayed. The flags are made to a strict design and are constructed and packaged up on a sort of conveyor belt system of protein production. This involves the flag being folded up in a certain sequence. Just like quality control in a factory, if the product is not made correctly, it’s rejected – in this case, if the flag isn’t folded correctly, the cell’s monitoring system is alerted and destroys it.

Dr Antony Antoniou, Arthritis Research UK non-clinical career development fellow, explains what happens in certain inflammatory forms of arthritis such as ankylosing spondylitis (AS): “For some reason, when individuals have a certain genetic make-up that makes them susceptible to arthritis, misfolding of these flags can occur. This may give the wrong signal to the immune system and allows it to destroy healthy cells. We know that in cystic fibrosis there is a defect in a protein folding process – does the same thing apply in ankylosing spondylitis?”

Ankylosing spondylitis – an elusive disease

It’s been known for over 30 years that ankylosing spondylitis is very strongly linked with one specific flag called HLA-B27. Despite this, and after many years of dedicated research, the disease process still isn’t understood. Although anti-TNF therapy does make a difference to some ankylosing spondylitis patients, the condition, unlike rheumatoid arthritis, hasn’t benefited from new therapy developments.

Dr Antony AntoniouResearch in the first Arthritis Research UK research fellowship awarded to Dr Antoniou confirmed that HLA-B27 flag folding problems do occur in ankylosing spondylitis patients. A second research fellowship which began early in 2009 is continuing the investigation.

“Our studies in both animal models and human cell lines show that individuals with the HLA-B27 gene have this flag folding problem,” explains Dr Antoniou. “At each stage of the conveyor belt model in the cell, there is a molecular ‘specialist operator’ that helps to put together and package each process in the system. It’s possible that one of these is not functioning properly and we need to check each one. If we can find where the system goes wrong, we may be able to develop a therapy that will correct it. Chemical operators have already been developed that work in the test-tube and we hope to develop one that can be put into the ankylosing spondylitis flag production system.”

An infection trigger?

Another research focus is examining how environmental factors affect ankylosing spondylitis development. It’s known that as well as gene susceptibility, microbial infection may affect flag folding, but how it does this is uncertain. “Animals with the HLA-B27 gene don’t develop flag folding problems if they are raised in germ-free environments,” says Dr Antoniou. “Also, Salmonella organisms like to live in cells that have active HLA-B27 genes. Why is this? We’re currently tagging Salmonella microbes with fluorescent markers so that we can track what happens to them in individual cells. It may be that infection is one of several factors contributing to the flag folding problems.”

Controlling bone erosion

Professor Tim Arnett and studentsBone loss is a serious problem in joint and bone diseases. Its control is still poorly understood although it’s known that many factors influence its development and progress. One of these factors was discovered almost by accident during research in the 1980s. Professor Timothy Arnett, in the Department of Cell and Developmental Biology, recounts how his earlier postdoctoral research had a surprising outcome: “We were trying to culture the cells that cause bone destruction – osteoclasts. They move across the bone surface, dissolving bone as they go. We had no success with the cultures, until we changed the acidity of the culture solution. When the culture medium was acidified, the osteoclasts ate away huge holes in the bone.”

Acid production affects bone loss

Acid production is a normal consequence of the metabolism of living cells, and in healthy individuals the body usually gets rid of excess acid. If the body can’t eliminate it efficiently enough however, it accumulates, resulting in acidosis (acid build up in the blood and tissues). This can result from kidney or lung disease, or can be due to a poor blood supply caused by inflammation or ageing. Acidosis increases the activity of the bone-destroying osteoclasts and this causes bone erosion.

Professor Arnett has also shown that low oxygen levels increase osteoclast activity. He explains: “In conditions of inflammation and swelling, the blood supply is restricted and tissue can be starved of oxygen. It starts to metabolise anaerobically, that is, without using oxygen – just like the muscles of endurance athletes do. This type of metabolism increases acid production and accelerates bone destruction.”

Acid sensors control bone erosion

How acid conditions influence osteoclast activity is the goal of Professor Arnett’s current research. He has discovered that these cells are extremely sensitive to even very tiny changes in acidity; how do they sense these changes?

“We’re looking at special receptors on the osteoclast cell surface that respond to changes in acidity,” says Professor Arnett, “to see how they regulate cell function. We will also study mice that have been specially bred to lack these receptors and examine their bone formation using a new state of the art micro-scanner.”

Professor Arnett thinks that the acid-sensitive receptors can be blocked by drugs to prevent their activation. In the longer term, this approach offers potential for the development of new drug therapies that may prevent or slow down bone destruction in bone erosion conditions such as rheumatoid arthritis.

Focus on Birmingham

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With funding of more than £1 million from Arthritis Research UK, the Rheumatology Research Group at the University of Birmingham is committed to tackling rheumatoid arthritis – the earlier the better.

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