Back to basics
Published on 01 January 2009
In the final part of our three-part series on the work of the Kennedy Institute of Rheumatology, Drs Yoshi Itoh and Richard Williams explain their research to Gillian Riley.
Rheumatoid arthritis and cancer: a shared approach
It may be surprising to learn that, even though the two diseases are quite different, there are striking similarities between the underlying processes that contribute to the development of rheumatoid arthritis (RA) and cancer. Both involve the migration of cells to an area of the body remote from where they are formed, and the development of abnormal cell metabolism that results in the destruction of healthy tissue.
Finding out how to stop this migration and abnormal cell function is the focus of one research project underway at the Kennedy. Dr Yoshifumi (Yoshi) Itoh, principal investigator of this Arthritis Research UK-funded research initiative, previously worked in cancer research programmes at the University of Tokyo where he extensively studied many common factors between cancer and arthritis development. He is optimistic that applying knowledge gleaned from cancer studies can fast-forward RA research.
Most people think of RA as a disease that locates in certain areas of the body. So how do migrating cells fit into the RA story?
Dr Itoh explains: “In the arthritic joint, the synovial lining becomes inflamed, eventually forming thickened and overgrown tissue known as synovial pannus tissue. This synovial tissue is essentially an invasive cellular tissue that extends over the cartilage. It is very destructive because, like cancer cells, the synovial cells produce enzymes that destroy the tissue they are penetrating, in this case cartilage, and eventually bone. We think that if we can stop this enzyme activity, we may be able to halt joint invasion and destruction.”
The invasive nature of the synovial tissue is really striking. The front line of the invading synovium is known as the ‘invasion front’ and the cells localised on this line are responsible for breaking down the key structural component of the cartilage matrix, which is a protein substance called collagen. Cartilage and bone are actually difficult structures to invade, but the invasive synovial cells secrete enzymes that literally dissolve their way through them.
“We have discovered that one of the enzymes produced by the invasive synovial cells, called MMP-14, is the key enzyme responsible for collagen degradation during invasion,” explains Dr Itoh. “When we analyse localisation of this enzyme in tissue sections, we can see that it is always highly expressed at the invasion front.”
He has tested out the destructive action of invasive synovial cells freshly isolated from synovial tissue by incubating them on thin collagen layers. Within just a few days of incubation, the synovial cells have melted down the collagen layers. He also embedded fresh synovial tissues within a collagen gel, and in three days, numerous synovial cells started to invade into collagen gel. He explains: “The invasive activity of synovial cells is MMP-14-dependent, and specific inhibition of MMP-14 completely halted the invasion process.”
The enzyme MMP-14 is a good target
MMP-14 is also produced by invasive cancer cells, and a US cancer research programme has recently developed an MMP-14 inhibitor. Collaborative work between the Kennedy and the US team will support the development of an inhibitory antibody for potential use in RA.
“We now know that this enzyme is a good target for therapy development,” says Dr Itoh. “If the drug development programme continues to be successful, we may have a therapy that could halt synovial invasion. We need to inhibit just this specific function so that we don‘t interfere with any others that may be beneficial in the body. Further research will determine what other functions this enzyme is involved in and whether or not we need to preserve them.”
He adds: “Ideally, it would be particularly beneficial to use an inhibitory drug like this early on in disease development. But that would depend upon obtaining a good diagnostic system, and of course, upon costs.”
An immunological approach - exploiting natural inhibition
One of Yoshi’s close colleagues, senior lecturer Dr Richard Williams, is investigating two major research areas that are exploring how the body’s immune system might be exploited to control disease mechanisms.
He has established that a special receptor molecule on the surface of some cells, particularly those in the immune system, may function to dampen down inflammatory functions - in other words, act as a brake on inflammation. This may be a natural way for the body to keep inflammatory reactions in check. In experimental models, administration of the receptor molecule, called CD-200, halts the progress of arthritis and has been reported to block TNF (tumour necrosis factor) production in the joint with an efficacy similar to that of anti-TNF therapy. Since anti-TNF therapy is considered the new benchmark in inflammation control, this is an extremely encouraging finding.
Therapies to block T-cell activity have been rather disappointing
Dr Williams comments: “There is no evidence that CD-200 is under-produced in arthritis but it would be useful if administering more of it would increase its inhibitory effects upon inflammation. It is an existing natural inhibitor and our aim is to see if boosting levels will improve its anti-inflammatory effect. Its function in humans has not yet been studied but it is hypothesised that it will have a similar role. Very little is known about CD-200 and our future research will concentrate on investigating the detail of this molecule and its functions.”
Dr Williams’ second research area focuses on T-cell activity. T-cells are a type of white blood cell (or lymphocyte) responsible for immune defence. There are different sorts of T-cell, all with different functions, and it is generally accepted that T-cell function, or rather malfunction, is a major cause of the excessive inflammation in RA.
However, Dr Williams points out: “Unfortunately, therapies designed to block T-cell activity have been rather disappointing in clinical trials. We now know that there are two different kinds of T-cell influenced by such therapies: ‘bad’ T-cells, or effector cells, that increase inflammatory effects, and ‘good’ T-cells, or regulatory cells that increase anti-TNF cell activity. The overall effect in terms of inflammatory reactions will be affected by the balance of their actions. Earlier therapies inhibited both types of cell and so probably didn’t alter the overall effect significantly. What we need is a completely different approach that will activate the regulatory cells alone.”
Studies have shown that a cell receptor called CD3 may be the key to achieving this. Using an inhibitor to this receptor appears to increase ‘good’ T-cell activity and blocks ‘bad’ T-cell activity. If the T-cell ratio can be normalised, the ‘good’ regulatory T-cells might be able to emerge and take a prominent role. Already tried and tested in patients, anti-CD3 therapy has been used to counter inflammation in organ transplant programmes, and has shown encouraging results in treating Type 1 diabetes patients.
“Now it’s important to establish whether this approach will be effective in RA,” says Dr Williams. “Initial studies in animal models show that a single injection of very low-dose drug produced long-term suppression of arthritis. We need to analyse exactly how the drug is working and then test it in clinical trials, starting off with low doses and building up slowly.”
“As with CD-200, an attractive aspect of this therapy,” he adds, “is that it stimulates a natural inhibitory mechanism to re-establish the immune system balance. Diabetes studies have shown that just one treatment can achieve long-term effects. If this is successful in arthritis, it would offer an advantage over existing therapies, such as methotrexate and anti-TNF, where treatment has to be frequent and long-term.”