The success of chemokine receptor antagonists as therapeutics will depend on a number of factors. It is clear that CCR5 antagonists will probably pave the way as the first approved chemokine drugs to treat disease in man. Here the situation is quite clear. The AIDS virus, HIV, utilizes CCR5 as a coreceptor to gain entry into the cell, and interfering with this process is likely to be of benefit in infected individuals. In autoimmune diseases, the utility of chemokine receptor antagonists is currently less clear. Why have several approaches from pharmaceutical industries targeting different chemokine receptors failed? Were the wrong receptors targeted? Did poorly correlative animal models of human disease mislead them? Did they fail because they are complex diseases in which several chemokine receptors, acting in concert, drive the pathophysiology? The list of possible reasons for the failure of these approaches could by itself fill an entire review, and it is apparent that we will need to consider these and many other questions and obtain answers to them if we are to make any real progress in bringing additional chemokine receptor antagonists to market.

Despite the failures discussed above, we remain cautiously optimistic that chemokine drugs can be of benefit in man. Their ultimate success, however, will depend on our ability to more clearly understand the role of chemokine receptors in driving the pathophysiology of complex autoimmune diseases than we currently do. This coupled with a parallel understanding of the animal models used as predictors of the human disease will also need to be more appreciated. Finally, much better clinical markers of the disease process in man will also be required not only to set up clinical trials more intelligently but also ultimately to monitor their progress. If we can make real progress in coming to grips with the issues discussed above, we might finally realize the promise of chemokine receptor antagonists as registered drugs.

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