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Remodelling the eye

18 November 2003

Professor Andrew Dick, Head of the University's Division of Ophthalmology, reveals some of the exciting research that may result in new treatments for eye disease.

Improvement in future health care relies heavily on translating advances made in the research laboratory into real treatment in the clinic. So above the waiting rooms at Bristol’s Eye Hospital, a purpose-built modern speciality hospital, sit the laboratories of one of the leading eye research centres in the country – Bristol University’s Division of Ophthalmology. Additional research laboratories, housed in the Medical School, were opened in July by Prince Michael of Kent, patron of the National Eye Research Centre.

Innovative research extended the storage time of corneas to a month

The Bristol Eye Bank, part of the University’s Division of Ophthalmology but funded by the Department of Health, issued its first corneas in March 1986 and is now the country’s largest eye bank. In the UK last year almost 2,300 people had their sight restored through a cornea transplant – two thirds of which were supplied by the Bristol Eye Hospital. Its Director, Professor John Armitage, was instrumental in establishing this facility. Pertinent to its success was the fact that it was the first eye bank in the UK to use a new method of storage for corneas – organ culture.

When one thinks of organ and tissue storage for transplantation, there is an assumption that they are frozen. In the case of corneas, however, laboratory and clinical studies have demonstrated that the action of freezing can cause significant damage. The one alternative – refrigerated storage – allows corneas to be kept for a few days, but Armitage’s innovative work introduced methods of storing corneas in a nutrient medium at close to normal body temperature, extending their storage time to a month. This not only greatly reduced wastage of valuable corneas, but helped to transform routine corneal transplantation in the UK from an emergency out-of-hours procedure to a scheduled operation that could be planned well in advance, to the benefit of both patients and hospitals. Importantly, doctors also have more time to find the most suitable patient for each cornea, which results in better grafts.

Nevertheless, cryopreservation (freezing) of the cornea offers the only truly longterm method of storage for corneas, and Armitage’s group is currently investigating the feasibility of ice-free cryopreservation by vitrification. When a liquid vitrifies (turns to a ‘glass’ without any ice forming), it does not undergo a phase change – such as when water turns into ice – but it acquires the physical properties of a solid owing to an enormous increase in viscosity during cooling. As a result, the mechanisms of injury associated with the formation of ice are avoided. But to attain this state requires exposure of cells and tissues to very high concentrations of solutes so work is ongoing to discover what solutions are most suitable.

But having retrieved a cornea and successfully restored the sight of your patient is by no means the end of the story. While most corneal grafts last for many years, 25% survive less than five years, resulting in the need for a second corneal transplant, which is likely to survive an even shorter time. One of the main causes of corneal graft failure, as with other transplants, is rejection of the foreign tissue by the immune system. To understand why this happens, a very large multi-centre study of corneal transplants – over 1,000 grafts – is in progress under Armitage’s supervision. Ultimately it is hoped that it will provide answers to questions such as whether tissue matching is required, the need for immune suppression, and whether it is possible to predict which patients are more likely to reject their transplants.

A 70% response rate in patients not responding to conventional drugs

Another area of research is Professor Dick’s programme that looks at how cells in the retina control inflammatory responses. There is a disease in humans called ‘uveitis’ (pronounced UV-itis), which is an autoimmune disease similar to arthritis or multiple sclerosis. Inflammation is caused by the body attacking tissue when the autoimmune response is turned on. In uveitis it attacks the retina, resulting in a 25% chance of losing your sight.

It is well known that in rheumatoid arthritis a small protein called ‘tumour necrosis factor’ (TNF) is released by cells, causing the violent inflammatory response. Using animal models, Dick’s team showed that TNF is also a promoter of inflammatory responses in the eye. In collaboration with colleagues in Oxford who designed what is called a ‘fusion’ protein which binds to the TNF and neutralises it, the team in Bristol then established its effectiveness in experimental models. They have now just finished their first highly successful clinical trial, testing it in patients with uveitis. The outcome was a 70% response rate in patients who were not responding to conventional drugs. As a result the team is negotiating with biotech companies to develop a drug to inhibit uveitis.

Another aspect of this research is looking at the way the retina itself controls inflammatory responses by the cells inside it. Macrophages are specialised cells of the immune system, designed to facilitate immune responses to prevent excess tissue damage and then mop up the rubbish. Collaborative work with industry, DNAX Inc in USA, is investigating mechanisms to generate compounds and drugs to facilitate repair of the retina, so that it may be possible to return inflamed tissue to its original state by controlling the macrophage function.

Finally, and perhaps most excitingly, the most recent development in ‘remodelling’ is with neural progenitor cells, or stem cells. In the brain these progenitor cells can be ‘switched on’ to generate a range of cell types required to repair damage to the brain. But although the retina consists of neural (nerve) tissue that is similar to the brain, it has always been understood that it does not contain progenitor cells that would help remodel the system. Dick, however, found this difficult to accept and in a paper published in September’s issue of the British Journal of Ophthalmology he and his team report the very first evidence of progenitor cells in the retina. This is an extremely important landmark that might ultimately lead to a whole new area of treatment for retinal disease.

Already they have a research programme that has been able to grow progenitor cells from biopsies of human retina, and are looking at what conditions are required to turn them into nerve cells, supporting cells of the retina, or photo receptor cells. If they can understand that, then they are well on the way to controlling eye disease by helping the injured retina to restore itself.

Professor Andrew Dick

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