Professor Foo ('Eddy') Liew is a man who has seen both sides of Wellcome. For 14 years he was at the Wellcome company's research laboratories at Beckenham. Driven by a desire to return to academia, in 1991, he accepted a post as Gardiner Professor of Immunology at the University of Glasgow, with programme funding from the Wellcome Trust. He is thus one of those rare people moving from industry to academia - "I'm rather unconventional in this country," he laughs.

Professor Liew was head of immunology at Wellcome and one challenge at Glasgow was to revitalise its immunology department. Having turned a department rated 3 in the Research Assessment Exercise into a 5* last time around, he can reasonably claim a mission accomplished. In terms of his own research, a growing interest in the regulation of the immune response is having exciting implications for the treatment of inflammatory diseases such as rheumatoid arthritis.

NO future

Starting in Glasgow, Professor Liew initially concentrated on the then flavour of the month, nitric oxide (NO). NO has been implicated in a whole host of processes, from control of blood pressure, timing of labour, and killing of parasites. Professor Liew wanted to know how NO was involved in defence against the intracellular parasite Leishmania, which causes disfiguring ulcers and other ill-effects. More intriguingly, how did Leishmania evade these defences and survive in the host?

It turns out that the parasite has evolved strategies to interfere with the host's immune response. A particularly cunning trick is to block the action of one of the molecules that signal between cells of the immune system - cytokines. By inhibiting a cytokine known as interleukin 12 (IL-12), Leishmania prevents the host from coordinating an immune attack.

What Leishmania has evolved to do - interfere with cytokine signalling - has now been adopted as a therapeutic strategy. For Professor Liew the turning point was a get-together for immu-nologists in Italy. "In 1995 I went to a conference in Florence, a cytokine conference, where I heard for the first time a gentlemen called David Cosman, from Immunex. He presented data for the first time about IL-15." This was big news for the cytokine community - only 14 interleukins were known at that point.

Dr Cosman described what he knew about his new molecule. "The gist of his story that stuck in my mind was that IL-15 was very similar to IL-2. At that time across the corridor from here was a gentleman called Peter Wilkinson, who was probably the world's authority on cytokines and cell migration and he'd been telling me for a long time that IL-2 is perhaps the most powerful cytokine for T cell migration. So I thought, let's do an experiment and see if IL-15 does the same thing."

Dr Cosman was happy to provide IL-15, and Professors Liew and Wilkinson set about testing its effects, in a five-week burst of work. Sure enough, IL-15 had a powerful effect on T cell migration. "It was one of the most satisfying papers for me," recalls Professor Liew, "because Peter does everything himself. So the paper, published in the Journal of Experimental Medicine in 1995, was just 'Wilkinson and Liew', two ageing professors, no technicians, no students, no postdocs!"

IL-15 was beginning to look very interesting. The story took another twist when a PhD student in Professor Liew's lab became involved. Iain McInnes, a clinician, was training to be a rheumatologist." I remember he told me that nobody knows how T cells migrate into the joint, as there's hardly any IL-2 in the joint. So I said, aha, it must be IL-15 then." Professor McInnes (as he is now) took a look. "Sure enough, there was IL-15 in the synovial joint of rheumatoid arthritis patients but not in osteoarthritis patients."

Exploring further, the two discovered that IL-15 was activating T cells in contact with macrophages within the joint, stimulating the macrophages to produce TNF-alpha - a molecule known to be important in the inflammatory damage seen in rheumatoid arthritis.

Enter Genmab

The results were published in Nature Medicine in 1996 and 1997. Then, a few years later, a Danish company called Genmab made contact. Genmab specialises in making fully human antibodies (generally regarded as superior to mouse antibodies since they will not be recognised as 'foreign'). Genmab had antibodies to IL-15, which showed promising effects in test-tube, and wanted to explore possible effects on cells from rheumatoid patients.

Returning from the USA, Professor McInnes was excited to hear this news: if the antibody blocked the action of IL-15 in the lab could it have a similar effect in the body - and prevent the development of rheumatoid arthritis?

Genmab carried out a phase I/II clinical trial, with 30 RA patients in several different countries. Professor McInnes coordinated the Glasgow arm of the trial. The 30 patients are in a bad way says Professor Liew: "They are refractory to all conventional disease-modifying anti-rheumatic drugs."

The results, though limited so far, were enormously encouraging: 63 per cent felt 20 per cent better, 38 per cent felt 50 per cent better, and 25 per cent felt 70 per cent better. The results are in line with those achieved with anti-TNF-alpha antibody trials, the most advanced of the new breed of cytokine-interfering antibody-based therapeutic agents. The US biotech company Amgen recently decided to exercise its commercialisation options with Genmab for the IL-15 antibody programme.

"This is a very clear example of what we call from bench to bedside," says Professor Liew. In seven years, curiosity-led research has led onto a very promising therapy. It is, he suggests, testament to the benefits of getting scientists working closely with clinicians: "It's a pretty powerful combination."

It's a model he will be developing further in a new building financed by the Joint Infrastructure Fund, construction of which began in September. On the ground floor will be structural biologists; on the first floor researchers from the Wellcome Centre for Molecular Parasitology; and above them the immunologists, a mix of basic and clinical scientists. "This will be a powerful research centre housing 300 scientists in 25 internationally recognised research groups," says Professor Liew, who is Director of this new Glasgow Biomedical Research Centre.

More interleukins...

Even top immunologists are struggling to keep on top of interleukins - now up to IL-30. "For a long time it stuck at 18," recalls Professor Liew. "For five years there were no new cytokines so people thought, 'that's it, finito, no new cytokines'. But then the human genome thing came through..." With the full sequence available, researchers could sift through the data looking for genes resembling those of interleukins. Up popped another dozen.

But it was IL-18 that caught Professor Liew's eye. A Japanese group showed that it could stimulate the production of pro-inflammatory cytokines. The Glasgow team set about seeing if it too might be involved in rheumatoid arthritis. They came up trumps again, and IL-18 is now being targeted in clinical trials.

Even that is not the end of the story. With two further components of the innate immune response also under scrutiny as possible targets for anti-inflammatory agents, inroads are finally being made into this previously intractable disease. "Our assumption is that inflammatory disease is not a single disease," says Professor Liew. "The pathology and the factors inducing it are multifactorial and cytokines are some of the key players. I use cytokines in the plural because there will be several cytokines acting synergistically or on their own - TNF-alpha is clearly important, IL-15 is one, IL-18 - there may be more. Some patients will be responsive to one type of treatment and the others may need others. So we are increasing our arsenal for these diseases, we're putting more and more into the armoury."

See also

• Professor Foo Liew at the University of Glasgow: Research interests
• Professor Iain McInnes at the University of Glasgow: Research interests
• Genmab: Danish biotechnology company that creates and develops human antibodies for the treatment of life-threatening and debilitating diseases.
• Genmab news release (4 September 2002)
  Results from Phase I/II multi-dose trial for rheumatoid arthritis
• Glasgow Biomedical Research Centre: News article (January 2002) features details on the building's development
• Medical News Today: Scientists discover genetic marker responsible for two-fold increase in risk of rheumatoid arthritis

Further reading

Wilkinson P C, Liew F Y (1995) Journal of Experimental Medicine 181: 1255-9

McInnes I B et al (1996) Nature. Med. 2: 175-82

McInnes I B et al (1997) Nature. Med. 3: 189-95

McInnes I B, Liew F Y (1998) Immunology Today 19: 75-80

Gracie J A et al (1999) Journal of Clinical Investigation 104: 1393-401