The strategy of blocking the chemokine system to combat disease

One of the key characteristics of inflammation is the recruitment of leukoc ytes to the site of inflammation. Most anti-inflammatory strategies act int racellularly on the target cells, but after the cells have migrated to the site. We therefore propose that the prevention of cellular recruitment by b lockade of the relevant chemokine receptor/ligand pair would present a nove l therapy in that it would act upstream of the therapies currently in use. The chemokine system is a complex family of over 40 ligands and 18 receptor s and as such may appear difficult to inhibit selectively. In the first par t of the article we discuss the specificity mechanisms that are beginning t o be unraveled which we believe occur at multiple levels. These levels of c ontrol of specificity include the temporal regulation of both the ligands a nd their receptors, which are under the control of pro-inflammatory cytokin es; the localization of chemokines on cell surfaces through their interacti ons with glycosaminoglycans; differential receptor/ligand interactions; and different patterns of receptor trafficking, to name but a few. The chemokine system has been validated as providing good therapeutic targe ts by several approaches. In our laboratory, we have used a chemokine recep tor antagonist in models of inflammation in vivo to demonstrate that this a pproach is successful in reducing inflammation. Chemokine receptors belong to the class of seven transmembrane spanning receptors, which have proven t o be excellent targets by the pharmaceutical industry for many diseases. Th e number of small molecule inhibitors of chemokine receptors is rapidly gro wing in the patent literature, and reports both in the literature as well a s conferences in the field have shown them to be effective in inflammatory disease models, as well as inhibiting HIV-1 infection. Since clinical trial s will begin this year with some of these molecules, hopefully we will fair ly soon have the answer of the efficacy of this therapeutic approach.