Equine Science Update
Reports from the world of  equine research.
Joint medication : the future.
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Improved understanding of the  mediators of inflammation in equine traumatic arthritis and osteoarthritis has led to identification of new targets for therapy, according to Professor Wayne McIlwraith.

Joint disease is a common cause of lameness in horses.  Inflammation within the joint tends to cause degeneration of the cartilage, which may ultimately result in osteoarthritis .

The control of the inflammatory process is very complex. Chief among the pro-inflammatory mediators in the joint is Interleukin-1 (IL-1).  IL-1 attaches to  specific receptors  and stimulates a cascade of other inflammatory mediators such as the matrix metalloproteinases (MMPs) and aggrecanases.

Normally, these pro-inflammatory mediators are kept in check  by various regulatory factors.   For example , the anti-inflammatory cytokines promote the production of interleukin-1 receptor antagonist (IL-1Ra), which blocks the inflammatory effect of IL-1.                                                                                                                                                                                                                                                                                                

This presents an opportunity to influence the inflammatory process in the joint. By boosting the  IL-1Ra concentration in the joint it should be possible to “switch-off” inflammation.

In 2003, Meijer and others demonstrated  that by culturing blood with chromium-coated glass beads, it was possible to produce a significant increase in the concentration of anti-inflammatory cytokines in the (human) blood.

Blood is collected into a syringe containing glass beads coated with chromium sulphate. It is incubated for 24 hours and then centrifuged to separate the serum.  Research with human blood shows that this Autologous Conditioned Serum (ACS) has markedly increased (140x) levels of IL-1Ra.  Levels of other anti-inflammatory substances are also increased. There is no change in substances such as IL-1betaand TNFalpha that promote inflammation.

Studies in humans have shown promising results. The ACS has been used to treat osteoarthritis , rheumatoid arthritis, and spinal and muscular problems. As the patient gets their own serum back again, the risk of adverse reactions is reduced.

Speaking at the 2006 British Equine Veterinary Association Congress, Dr McIlwraith described how they have evaluated the use of ACS in horses in his laboratory. Eight horses with experimental osteoarthritis were treated with ACS. Eight more horses were treated with saline only.                                                                                                                                                                                

They found a significant reduction in lameness for as long as 72 days. However, they had difficulty detecting IL-1Ra in the ACS. This was probably because they had been using a test based on human blood to detect it. When they changed to a test based on mouse antigen to detect the IL-1Ra, they were more successful.  They were able to see an increase in IL-1Ra- but the change was still not nearly as dramatic as that shown in human blood. “But we don’t know yet how much cross-reaction we are getting with the mouse antigen”

So ACS gives improved clinical signs, though it is not yet certain (in the horse) what factors are present in the “soup”.  There is some evidence for an increase in IL-1Ra. The clinical results are very encouraging.

According to Dr McIlwraith, ACS will fill a need for post-operative therapy in mild to moderate osteoarthritis and cases not responsive to corticosteroids. “It is likely to be part of our armamentarium until we get gene therapy sorted out.”

Gene therapy offers another way of increasing the IL-1Ra concentration in the joint. By injecting a virus containing the genetic code for production of IL-1Ra it is possible to increase the production of IL-1Ra within the joint.

“I feel that gene  therapy is going to be the answer” he says , “ but we need a better vector.” The problem is that the adenovirus that is used to introduce the genetic code into the joint does cause some immune-mediated reactions.  But research is continuing.  McIlwraith is optimistic that they will find a better vector. “This will allow us to put gene therapy into practical clinical use.”

Reference:
The production of anti-inflammatory cytokines in whole blood by physico-chemical induction.
Meijer H, Reinecke J, Becker C, Tholen G, Wehling P.
Inflamm Res. (2003) 52; 404-407.

For more details on gene therapy see:
Gene therapy for equine joint disease.
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