The strategy of blocking the chemokine system to combat disease

One of the key characteristics of inflammation is the recruitment of leukocytes to the site of inflammation. Most anti-inflammatory strategies act intracellularly on the target cells, but after the cells have migrated to the site. We therefore propose that the prevention of cellular recruitment by blockade of the relevant chemokine receptor/ligand pair would present a novel 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 receptors and as such may appear difficult to inhibit selectively. In the first part of the article we discuss the specificity mechanisms that are beginning to be unraveled which we believe occur at multiple levels. These levels of control of specificity include the temporal regulation of both the ligands and their receptors, which are under the control of pro-inflammatory cytokines; the localization of chemokines on cell surfaces through their interactions 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 targets by several approaches. In our laboratory, we have used a chemokine receptor antagonist in models of inflammation in vivo to demonstrate that this approach is successful in reducing inflammation. Chemokine receptors belong to the class of seven transmembrane spanning receptors, which have proven to be excellent targets by the pharmaceutical industry for many diseases. The number of small molecule inhibitors of chemokine receptors is rapidly growing in the patent literature, and reports both in the literature as well as conferences in the field have shown them to be effective in inflammatory disease models, as well as inhibiting HIV-1 infection. Since clinical trials will begin this year with some of these molecules, hopefully we will fairly soon have the answer of the efficacy of this therapeutic approach.