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Issue 474, 3 December 2001

Rearming our immune systems to win the battle against disease

Illnesses and epidemics once thought curable are on the rampage again, as medicines become increasingly ineffective against drug-resistant strains of diseases such as TB and malaria. But why aren't our own immune systems able to defend us properly? Immunologist Professor Simon Carding believes his research team may have found an important piece in the puzzle of how our immune systems work, opening up new ways to treat a whole range of diseases.

Gamma Delta T-cells (GDT-cells) (pictured left) were discovered fifteen years ago, but their function has remained a mystery until now. They are found in all mammals, and earlier research showed they were often present in large numbers in patients suffering from infectious or autoimmune diseases, such as TB, malaria, listeriosis, rheumatoid arthritis, multiple sclerosis and coeliac disease. Scientists believed they were part of the problem, helping these diseases to progress, but Professor Carding believes that the GDT-cells are actually part of the cure.

One of the Leeds research team's particular interest is in tuberculosis, a disease which was virtually eradicated from the UK, but is a major killer in the developing world, with over two million deaths from the disease each year.

Contracting TB is very much determined by individual immune response: seventy percent of those who come in contact with the disease will eradicate the bacteria and show no signs of infection. There are nevertheless over eight million new cases of TB each year, many due to the AIDS epidemic, as AIDS is one of the most common reasons for those exposed or infected to develop the disease.

Professor Carding (pictured above) said: " Many of the symptoms shown by TB patients such as chronic inflammation are not directly caused by the TB bacteria, but rather by the immune system killing off healthy cells in the body. As such, TB has a lot in common with autoimmune diseases where the off switch for the immune system is missing or defective resulting in chronic inflammation.

In all these diseases, the key to better treatment might not be to directly attack the organism, but to find out why the immune system is unable to respond properly to the disease. We believe that the Gamma Delta T-cells may provide an answer."

When mice which are genetically deficient in these cells are infected with a bacteria, they show chronic inflammation and extensive tissue damage that results from the inability to switch off the immune response once the invading bacteria have been eliminated. To see if there is a correlation in humans, Professor Carding and his team have been working with clinicians treating large numbers of patients with advanced TB in China, Turkey, Mexico, the USA, Canada and Germany.

"Tests showed that patients start with normal levels of the cells, but lose them as the disease progresses. Patients who respond well to chemotherapy treatment see their GDT-cells return to a normal level. We believe if we can rearm the cells, then patients may be able to fight not only TB, but a whole range of diseases, more effectively."

The research team has found that the GDT-cells role is to kill off other cells called macrophages, the most important cells in the immune system. Macrophages perform various beneficial functions, such as destroying tumour cells, killing pathogenic microorganisms, and activating the immune system.

But they can also be harmful, producing toxic substances which damage or destroy healthy cells. Professor Carding's research team have shown that GDT-cells regulate the levels of macrophages by eliminating them once their job has been done, ensuring a balanced immune response.

Winning the battle – some members of Carding's research team: Charlotte Egan and Sheena Cruickshank (above left to right) and Sam Broad (below)

The scientists believe that the macrophages express a substance or antigen to which the Gamma Delta T-cells react. If the wrong messages go out, or if the GDT-cells fail to react, the immune response continues unregulated, causing tissue damage and chronic inflammation.

Professor Carding said: "If we can discover what triggers the GDT-cells, it will open the way to new treatments for auto-immune and infectious diseases. If the cells are still present, we could reactivate them. It will be harder to regenerate the GDT-cells if the disease actually kills them off, but it is still potentially possible."

The problem for the scientists is that the substance which triggers the GDT-cells could be one of many proteins or may not be a protein at all. Using a process of elimination, and informed guesswork to target likely candidates, the scientists are looking at certain molecules, extracted from the surface of the macrophages. Separated into constituent parts, these molecules are then tested against the GDT-cells and any possible reaction monitored.

If successful in finding this substance, the research could open up new forms of treatment, using the immune system itself to fight the disease and bypassing the problem of antibiotic resistance.

Professor Carding said: "Our current funding will run for around three more years, and we hope to have identified the antigens recognised by the GDT-cells by then. Forming treatments based on the research will take much longer."

The breakthrough has been well received by other research groups around the world, and Professor Carding has been presenting the findings at international meetings throughout Europe and the USA.

A full review of the research is to be published in Nature's immunology review next year.

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