Fighting rejection | Action Medical Research

Touching Lives - June 2005

Fighting rejection

“The cornea,” says Professor Andrew George, “is the window of the eye.” He points out that it is much thicker and tougher than ‘the transparent film’ that people imagine it to be, but whatever word you use, its transparency is critical to the ability to see.

A number of eye diseases can cause the cornea to become cloudy, with consequent partial or total loss of sight in one or both eyes. Such diseases can affect all age groups from the infant to the very old, including young adults. For most diseases causing corneal opacity, the only treatment at present is a cornea transplant. 3,500 cornea transplants are undertaken in the UK every year, and of those about 700-1000 will experience rejection by the immune system.

Squeamish readers should skip this paragraph. The operation involves removing the diseased cornea with a circular blade, called a trephine, rather like the drill bits you use to make very large holes in wood. A new cornea is dropped into the disc-shaped hole, and stitched up to the rest of the eye. It is the oldest type of transplant operation — in fact the technique celebrates its 100th anniversary this year. In 1905, a Middle European agricultural labourer was the first person to have his sight restored with a new cornea, transplanted by a surgeon called Zirm.

‘Rejection episodes’

Because it is such an established procedure, for a long time rejection of the new cornea wasn’t felt to be a problem. Rejection of alien tissue is a natural bodily function. From the body’s point of view, a transplant is an unnatural and invasive object, and the immune system will dispatch antibodies and effector cells (white blood cells which generate more antibodies) to see off the intruder if they possibly can — unless the body’s natural defences are thwarted by drugs or other techniques.

In the early days of kidney and liver transplants, there were large numbers of rejections withinthe first year. By contrast corneal rejection occurred — and still occurs — more evenly over a period of five years. Nevertheless ^about 20-30 percent of new corneas will undergo a rejection episode, to use the technical phrase, over that period.^

Firm friends

Professor Andrew George, an immunologist at Hammersmith Hospital, accepted the textbook view of cornea transplants until 1994. Then he met Frank Larkin, Consultant Surgeon and Director of the Cornea Service at Moorfields Eye Hospital, at a seminar he was holding on the subject of rejection. “Until I met Frank I’d never even thought about it. I asked him, ‘What are you doing here? You’re an ophthalmologist. This isn’t a problem for you.’”

Over lunch Frank convinced him that there was indeed a significant level of rejection, which he saw in his post-operative patients on a regular basis. From then on, the two men became friends and brought their combined disciplines to bear on solving the problem through a series of projects, several of which have been funded by Action Medical Research.

In their latest research, Andrew and Frank have been following the role of proteins calledchemokines, which act as both an alarm system and as pathfinders. They summon the antibodies and other cells and indicate where they should be attacking the intruder. The challenge was to find ways of disengaging the chemokines so that they didn’t ‘sound the alarm’.

Epstein Barr Virus

In order to do this, they asked themselves where in nature there was a mechanism which already did this successfully. The answer lay with viruses, which can exist within the body for a long time, and somehow dupe the immune system into not responding to the alien material. In particular they looked at the Epstein Barr Virus (EBV), and tried to find its recipe for success.

EBV manufactures a molecule called vMIPII. It looks like a chemokine, but it isn’t functional, and it doesn’t trigger antibodies or the inflammatory reaction which is part of expelling an invader.

So Andrew and Frank isolated the genetic material used to make vMIPII, and introduced it into the cornea, wrapped in fatty proteins. Once there, the cornea is induced to manufacture its own ‘false’ chemokines, and thus suppress the immune reaction. In transplant models this almost doubles the survival rates of transplanted corneas.

When a liver or heart is transplanted, it has to be delivered to the new host’ within 24 hours. Freshness is key. However, corneas can be stored for up to a month before transplantation into the eye. This creates an opportunity which Frank finds very exciting: “The fact that we have this breathing space means we can look at the possibility of modifying the cornea while it is in storage. It could go into the eye already treated and primed, with no invasive techniques involved other than the transplant itself. That’s practically impossible with all other kinds of transplant.”

Exciting possibilities

For Andrew, as an immunologist, this way of neutralising the chemokines opens up more possibilities: “I see it as a way in for other things. Once we’ve proved that this technique works with corneas, we can go on to see if it can be used with other transplants. Of course there will be delivery issues to consider, but it opens up a whole host of possibilities. I’d love to look at them, but of course we can’t do two things at once.”

In parallel with this work, Professor George also explored the role of a protein called IDO, which is present in the placenta and prevents the mother’s body from rejecting the fetus — another alien invader.

Professor George says, ^”We’re in the position now where we’ve got two possible strategies, and both of them are sort of half working. I’d like to move towards a situation where we can do a pilot study in patients at particularly high risk of rejecting a transplant^ — people with blood vessel growth in the cornea, patients who have already rejected a cornea or very young children.

“We need to try to restore sight quickly in children, because if we don’t the brain won’t get the stimulus it needs to create the proper neural paths required to be able to see. If you restore sight to an adult who’s been blind from birth, they won’t see properly because the brain won’t have the means of processing the information from the eye.”

Professor George has a close relationship with Action Medical Research, having recently joined the Scientific Advisory Panel which looks at new proposals for research and recommends priorities for funding. “Ophthalmology can be seen as the Cinderella of medical research. It’s a small field, and slightly off the mainstream. I’m very pleased that Action Medical Research is putting money into it.”

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