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Priming the immune response: new research is uncovering how the army of cells and proteins of the body's immune system might be targeted to treat a range of blinding eye conditions.

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IN THE soup of cells, lipids, proteins, nutrients and waste products pumping through the body's circulatory system, the cellular sentries of the immune system keep a constant watch. Unlike their passive red counterparts, white blood cells are very much active, churning out antibodies and destroying invaders.

Supporting them is a vast infantry of protein helpers which are crucial in allowing the immune system to identify what is a healthy part of the 'self' and what has the potential to turn into something nasty.

Scientists are beginning to uncover how the same set of defences the body uses against invaders also regulates aspects of cell growth, keeping track of the development of structures and targeting them for removal when it goes things go awry.

Regulating vessel growth

Proliferative retinopathies are one area in the research spotlight. Conditions such as retinopathy of prematurity or advanced diabetic retinopathy are a major source of sight loss. But the body has its own mechanisms to fight back and to clear out the abnormal blood vessels, which develop in these conditions. It was known that the immune system was involved, but exactly what role it played was not fully understood.

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Dr Kip Connor, assistant professor of ophthalmology at the Massachusetts Eye and Ear Infirmary in Boston, explained the trouble with new vessels in retinopathy of prematurity. "When babies are born prematurely, the vasculature system of their eyes isn't fully developed," he said. "But unfortunately, the vasculature system of the lungs is also underdeveloped, so we put them on high oxygen to help maintain normal physiological oxygen levels.

"This high oxygen level affects the retinal blood vessels... so the retina thinks 'I have enough oxygen, I don't need to grow these normal vessels'." It is when the babies are returned to the normal atmospheric environment that the problems occur. The drop in oxygen levels leads to a flourish of abnormal blood vessels in the eye as they grow to catch up, this can lead to bleeding, scarring and in severe cases, detachment of the retina.

By putting premature mice in a high oxygen atmosphere for five days and then returning them to normal oxygen levels, Dr Connor and colleagues were able to mimic the conditions of the disease. They found that in mice lacking an innate immune system, the new vessels were more abundant and were maintained longer by the body. However, control mice with a functioning immune system developed far fewer abnormal vessels and the new vessels were singled out for destruction.

Recognising 'self'

The evidence pointed to a highly conserved part of the innate immune system, called the alternative complement pathway. It is this pathway, says Dr Connor, that is responsible for identifying and targeting the abnormal vessels for removal while leaving healthy blood vessels intact, and could provide new targets for therapies.

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"Normally the endogenous complement system would see these vessels as abnormal and target them," explained Dr Connor. "But what we saw when we knocked [the system] out, is that this didn't happen and we saw a more severe disease phenotype that persisted longer."

By scanning for proteins on the outside of cells, the immune system can identify which cells are 'self' and are healthy. One of these surface proteins, CD55, was found on the cells of healthy blood vessels. However, the protein was lacking on the cells of new abnormal vessels. The lack of protein highlights a gap where the cell should be, the 'missing self', so they are targeted by the immune system for removal. "We found that these new vessels down-regulated [CD55] as they sense that they are growing abnormally, and that allows them to be targeted," said Dr Connor.

The effect was also shown in human cells taken from the umbilical cord, explained co-researcher and post-doctoral research at Massachusetts Eye and Ear, Dr Harry Sweigard. "Just the exposure to the low oxygen levels was enough to lower the CD55 expression," he told OT. The group now hopes that the findings can be translated into a nondestructive method for targeting new blood vessels, while leaving healthy tissue intact.

Targeting AMD

Also found among the arsenal of proteins used by the immune system are the inflammatory mediators. These messenger proteins, called cytokines, issue the chemical call to action and act as beacons to direct white blood cells to where they are needed. One of these messenger proteins, IL-18, may provide a promising new treatment for age-related macular degeneration (AMD).

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Researchers at Trinity College Dublin used a form of IL-18 currently being trialled in cancer patients to stop the growth of new blood vessels supplying tumours. Their work builds on previous research which alluded to a protective role of the protein, and demonstrates that it may help to control the formation of blood vessels in the neovascular 'wet' form of the condition. Although IL-18 has a known role in inflammation in the body, it was found to suppress the growth of new vessels in the eyes of mice without damaging the retina.

Using a standard mouse model--used in the preclinical development of current intravitreal AMD drugs--the team showed that systemic IL-18 was as effective as intravitreal injections at stopping new vessel growth, and provided added benefit as an add-on therapy.

Current treatments for AMD require regular intravitreal injections of antiVEGF to stop the growth of new vessels. However, while effective, there may not be an end point to treatment, with some patients reported to have received over 100 injections. The hope is that IL-18 could be developed as an add-on to existing treatments, or even as a standalone therapy.

Other groups have shown IL-18 to cause degeneration of the delicate RPE cells of the retina, but the Trinity group was unable to replicate these effects in cell cultures. The researchers propose that it is the over-expression of an immature inactive form of the protein, pro-IL-18, which may be responsible for the negative effects. The mature active form of IL-18 which they used plays a protective role by blocking the production of the growth factor which promotes new vessel growth (VEGF). To date, the only reported side effect in the clinical trials using systemic IL-18 is a low grade fever which resolves by itself.

Dual role

"In the mouse model, we can show it's as good, if not better than anti-VEGF therapy, on its own," explained Dr Sarah Doyle, assistant professor in immunology at Trinity. "And together, they work even better."

"We were initially concerned that IL-18 might cause damage to the sensitive cells of the retina, because it is typically linked to inflammation," she added. "But surprisingly we found that low doses had no adverse effects on the retina and yet still suppressed abnormal blood vessel growth."

The first move would be as an add-on to existing anti-VEGF treatment, but Dr Matthew Campbell, research assistant professor at Trinity, told OT that the approach could also move to trials for a standalone treatment. "If we can show efficacy in humans, then both of these options are on the table," he said.

"Around 30% of patients will eventually stop responding to anti-VEGF therapy, and long-term treatment may eventually begin to damage the cells of the retina," explained Dr Campbell. "So we do need more therapies, we need to keep exploring the molecular complexity of AMD and to identify new targets.

"I think this [work] is another stepping stone on that path to identify the targets, and then actually try to translate those into new forms of therapy."
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Author:O'Hare, Ryan
Publication:Optometry Today
Geographic Code:1USA
Date:May 9, 2014
Words:1251
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